3. What is meant by bioavailability of a drug? What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
Bioavailability : Active content of a drug enter the body systemic circulation for pharmacokinetic reaction.
1) Cyclosporin Take at a consistent time of the day (at 12-hour intervals). Starting dose at 4 to 10 mg/kg/day orally in two divided doses. Start at the lower end of the dosing range and make adjustments based upon therapeutic drug monitoring level.
Aiming 200 to 300 ng/mL in the first 3 months after transplantation then 50 to 150 ng/mL for subsequent months.
Tacrolimus Tacrolimus immediate-release form should be taken at a consistent time of the day, 12 hour intervals on an empty stomach. The extended-release products should be taken at the same time of the day in the morning. Tablet should not be chew, divide, or crush. Starting dose at 0.1 to 0.2 mg/kg/day orally in two divided doses. Start at the lower end of the dosing range and make adjustments base on serum drug level.
In patients who receive Thymoglobulin for induction therapy:
Aiming 7 to 10 ng/mL for the first month after transplantation then 3 to 7 ng/mL for subsequent months.
In patients who do not receive antilymphocyte-depleting agents for induction therapy:
Aiming 8 to 10 ng/mL for months 1 to 3 after transplantation then 3 to 7 ng/mL for subsequent months.
MMF Mycophenolate mofetil (CellCept) and enteric-coated (delayed-release) mycophenolate sodium (Myfortic) are not equivalent. Mycophenolate mofetil 500 mg is considered equivalent to mycophenolate sodium 360 mg.
Mycophenolate mofetil:
Route : Oral, IV:
Dosage : 1 g (range: 500 mg to 1 g) twice daily as part of an appropriate combination regimen
( EMMC 1999; Hardinger 2021; KDIGO 2009; TMMRT 1996; manufacturer’s labeling).
Mycophenolate sodium, delayed release:
Route : Oral
Dosade : 720 mg (range: 360 to 720 mg) twice daily as part of an appropriate combination regimen
(Hardinger 2021; KDIGO 2009; Salvadori 2004).
Azathioprine Route : Oral, IV. Dosage : 1 to 2 mg/kg once daily as part of an appropriate combination regimen (Cristelli 2013; Wüthrich 2000). manufacturer’s labeling recommends up to 3 mg/kg once daily; some experts do not exceed 150 mg/day (Remuzzi 2007).
AMAL Anan
2 years ago
Bioavailability is drug amount which reach circulation
Cyclosporine 35-45%
Tacrolimus 25%
MMF 94 %
dina omar
2 years ago
Bioavailability: amount of the drug that reach circulation unchanged in its active form
Oral Bioavailability = (AUCoral/ AUCintravenous) x 100%
Drugs Bioavailability ; Cyclosporine :
Bioavailability is 35 to 45 % , max blood concentration after 2 hours
Steady state level in 1 or 2 months.
Primarily eliminated in stool and bile ,
Better on empty stomach . Tacrolimus:
Bioavailability 25%
max blood concentration after 2 hours , Primarily eliminated in stool and bile
Better on empty stomach; before meals or after 2 hours MMF: Bioavailability is 94 % ,An enteric coated of MMF that is absorbed only in small intestine(Myfortic) is available with peak concentration after 2-3 hours . Better on empty stomach.Enzyme inhibitors increase its level as ; erythromycine , grape fruit , antifungal, verapamil, Azathioprine: Bioavailability 47% , max blood concentration after 1 to 2 hours , Primarily eliminated in urine , Better after meals.
Ahmed Fouad Omar
2 years ago
Bioavailability of a drug is the amount of the drug that reaches the peripheral circulation unchanged in its active form
The oral bioavailability of a drug = AUC oral/ AUC intravenous x 100%
Bioavailability of an oral drug depends on:
1) Gastrointestinal transit rate
2) First-pass metabolism and/or excretion by the gut/liver.
What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
Cyclosporine:
o Oral bioavailability: 30-45%, increases with time and reaches max concentration after 2 hr ((from here comes estimation of C2 level) and food decreases its absorption and hence better given on empty stomach
o Reaches a steady state in 4-8 weeks.
o Volume of distribution: 3-5 L/kg
o Primarily eliminated in bile and stool, only 6% in urine.
Tacrolimus:
o Oral bioavailability: 25%, max blood concentration is reached in 1-3 hours . Food decreases absorption, hence better to be given on empty stomach
o Volume of distribution: 0.68 L/kg.
o Primarily eliminated in bile and stool. Diarrhea may lead to increased absorption from lower GI tract increasing drug exposure and resulting in toxic levels.
MMF:
o It is a pro-drug with oral bioavailability: 94%, max blood concentration is reached in 2 hrs hours. However, a second peak occurs after 6-12 hours due to entero-hepatic circulation. Fatty diet decreases the absorption, so better given on empty stomach unless GIT side effects occur, so can be given during meals
o Volume of distribution: 0.71 L/kg. Eliminated in urine (93%).
o An enteric coated of MMF that is absorbed only in small intestine(Myfortic) is available with peak concentration after 2-3 hours. AUC of mycophenolic acid increases over time.
Azathioprine:
o Oral bioavailability is 47% , max blood concentration is reached in 1-2 hours. It is administered after meals to avoid GI side effects.
o Volume of distribution: 0.1 – 1.7 L/kg. References:
1)Hand book of kidney transplantation 6th edition
2) Srinivas TR, Meier-Kriesche HU, Kaplan B. Pharmacokinetic principles of immunosuppressive drugs. Am J Transplant. 2005 Feb;5(2):207-17
Hamdy Hegazy
2 years ago
What is meant by bioavailability of a drug? What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs? Bioavailability refers to the percentage of the drug that reaches the blood stream, it is calculated by the area under the curve relating the dose given via different routes and the drug level in the blood over a period of time. Drugs given via IV route have 100% bioavailability. Cyclosporine bioavailability: Food may decrease cyclosporine absorption. It should be taken in the same time related to meals, either with or without. There are different generic preparations with bioavailability differences between formulations. Oral dose is usually 3 times of IV dose. Ketoconazole is used to reduce the dose and the cost because it increases the blood level of cyclosporine. There is inter patient variability in absorption and drug-drug interactions.
Tacrolimus Bioavailability:Food decreases absorption of tacrolimus by 30%, Tacrolimus should be taken on empty stomach 1hour before or 2 hours after meal. There is intra-patient (effect of food, drug-drug interactions) and inter-patient variability (different activity of Cytochrome B450). There is different formulation of Tacrolimus. Oral dose is usually 3-5 times as IV dose.
CNIs drug interactions: 1- Enzyme inhibitors increase level of CNI: Calcium Channel Blockers: verapamil, diltiazem, and amlodipine. Antifungals: ketoconazole, fluconazole, and itraconazole. Antibiotics : erythromycin and clarithromycin. Grapefruit juice increase level of CNI. 2- Enzyme inducers decrease level of CNI: Anti-epileptics: phenytoin, carbamazepine and phenobarbiturates. Anti TB drugs : rifampin and INH.
Mycophenolate Bioavailability: Can be taken with or without food. Cyclosporine reduces the level of MMF, so the dose is usually higher (2gm daily) when MMF is combined with cyclosporine compared to when combined with tacrolimus (1 gm daily). Proton pump inhibitors reduces MMF absorption. However, they don’t affect enteric coated- mycophenolate sodium. Corticosteroids may lower the level of mycophenolic acid. Steroid free protocols use lower doses of MMF. Aluminum or magnesium hydroxide antacids reduce absorption of MMF Azathioprine Bioavailability: It is a prodrug, 50-70% of the dose is absorbed and 88% is converted to 6- Mercaptopurine, it is usually taken with or without food. TPMT activity should be checked before starting Azathioprine, recipients with deficiency of TPMT slowly metabolize Azathioprine, so they are liable to azathioprine accumulation and bone marrow suppression.
ahmed saleeh
2 years ago
Bioavailability: amount of the drug that reach the circulation unchanged in its active form
Oral Bioavailability = (AUCoral/ AUCintravenous) x 100%
Cyclosporine :
Bioavailability is 35 to 45 % , max blood concentration after 2 hours (hence C2)
Steady state level in 1 or 2 months.
Volume of distribution 5L/kg
Primarily eliminated in feaces and bile
Better on empty stomach .
Tacrolimus:
Bioavailability 25%
max blood concentration after 2 hours
Volume of distribution 0.68L/kg
Primarily eliminated in feaces and bile
Better on empty stomach.
MMF:
Bioavailability is 94 % ,
max blood concentration after 2 hours
2nd peak in 6 to 12 hours.
Steady state level in 1 or 2 months.
Volume of distribution 0.71L/kg
Better on empty stomach . Avoid with fatty meals.
Azathioprine:
Bioavailability 47%
max blood concentration after 1 to 2 hours
Volume of distribution 0.1 to 1.1 L/kg
Primarily eliminated in urine
Better after meals.
Tahani Ashmaig
3 years ago
☆Bioavailability of a drug:
_____________________________
Refers to the extent a substance or drug becomes completely available to its intended biological destination [1]
▪︎ It is a measure of how much a substance is able to access the circulation and reach the target area, and it depends on absorption (how much we get it) and secretion (how much we get out).
▪︎Bioavailability of a drug is largely determined by the properties of the dosage form, which depend partly on its design and manufacture. Differences in bioavailability among formulations of a given drug can have clinical significance; thus, knowing whether drug formulations are equivalent is essential.
☆Cyclosporine:
_________________
▪︎The bioavailability of cyclosporine is variable, ranging from less than 10% to 89% in various populations. As a result of its lipophilicity, cyclosporine is ⅞ distributed outside of the blood volume once it is absorbed. The volume of distribution ranges from 3 to 5 L/kg [2]
☆Oral bioavailability of tacrolimus:
_____________________________________
▪︎Vriable between patients, averages ;25%. This is largely due to extrahepatic metabolism of tacrolimus in the gastrointest
epithelium. Nevertheless, intra-patient variability is low, as evidenced by the small number of dose changes required to maintain patients within the recommended
tacrolimus target levels.
▪︎Tacrolimus is distributed extensively in the body with most partitioned outside
the blood compartment. Concentrations of tacrolimus in blood are used as a surrogate marker of clinically relevant concentration of the drug at the site(s) of action. Convenient whole-blood sampling within a
“2-h window around 12 h post-dose (Cmin) is highly predictive of systemic exposure to tacrolimus and is thus used to optimise therapy.
▪︎The interactions of tacrolimus with other immunosuppres-sive agents are well characterized.
☆MMF:
_________
▪︎Mycophenolate mofetil is rapidly absorbed in the small intestine.
▪︎The maximum concentration of its active metabolite, MPA, is attained 60 to 90 minutes following an oral dose. The average bioavailability of orally administered mycophenolate mofetil in a pharmacokinetic study is 94% [4].
☆Azathioprine:
__________________
▪︎Azathioprine is an immunosuppressive agent which functions through modulation of rac1 to induce T cell apoptosis, as well as other unknown immunosuppressive functions.
▪︎ It has a long duration of action as it is given daily, and has a narrow therapeutic index.
▪︎ Patients should be counselled regarding the risk of malignancies of the skin and lymphomas.
▪︎Mechanism of action: Is not entirely understood but it may be related to inhibition of purine synthesis, along with inhibition of B and T cells.
6-thioguanine triphosphate, a metabolite of azathioprine, modulates activation of rac1 when costimulated with CD28, inducing T cell apoptosis.
▪︎Humans Absorption
Oral azathioprine is well absorbed, with a Tmax of 1-2h.Further data regarding the absorption of azathioprine is not readily available.
▪︎Volume of distribution: Data regarding the volume of distribution of azathioprine is not readily available.
▪︎Protein binding: Azathioprine is 30%1bound to proteins such as human serum albumin in circulation.
▪︎Metabolism: Is converted to 6-mercaptopurine
▪︎The intestinal absorption of azathioprine ranges from 50 to 72% [5]
____________________
Ref:
[1] Price G, Patel DA. Drug Bioavailability
[2] Miles G. Choc. Bioavailability and pharmacokinetics of cyclosporine formulations: Neoral® vs Sandimmune®
. June 2008.
MICHAEL Farag
3 years ago
Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. Bioavailability of a drug is largely determined by the properties of the dosage form, which depend partly on its design and manufacture.
For intravenous route bioavailability is 100%, while in other routes of administration such as oral route it could be lower due to first pass effect.
Drug bioavailability after oral administration is affected by a number of different factors, including physicochemical properties of the drug, physiological aspects, the type of dosage form, food intake, biorhythms, and intra- and interindividual variability of the human population. Accordingly immunosuppressant agent should be monitored by assessing their blood level. Cyclosporine:
Mechanism of Action: Calcineurin inhibitor, suppresses cellular and humoral immunity (mainly T cells).
Forms: Modified (Neoral) and Non-Modified (Sandimmune).
Bioavailability: Modified (Neoral) has better absorption up to 30% and less dependant on food, bile acids and GI motility. Incomplete absorption of cyclosporine mostly related to the first pass effect. Absorption of cyclosporine is highly variable. Peak plasma time: Neoral 1.5-2 hr; Sandimmune 3.5 hr.
Distribution: Protein Bound: 90%, Volume of distribution (Vd): 13 L/kg.
Dose: 15 mg/kg/day PO divided BID Reduce 5% per week until: 5-10 mg/kg/day PO divided BID. if IV then third oral dose (5mg/kg/day).
Therapeutic window: Narrow, 500-600 ng/ml in the first week of post-transplantation, 600-800 ng/ml in the second week to sixth month of post-transplantation, 400-600 ng/ml in the seventh to twelfth month of post-transplantation and 350-400 ng/ml 1 year after post-transplantation.
Should taken consistently with relation to meals.
Tacrolimus:
Mechanism of Action: Calcineurin inhibitor; inhibits T-cell activation and proliferation, humoral immunity Macrolide antibiotic; potent immunosuppressant.
Bioavailability: 7-55% (children); 7-32% (adults). Peak plasma time: 0.5-6 hr. Has incomplete and variable GI absorption. Absorption is decreased by food 27%.
Metabolism: Metabolized in liver by CYP3A4, level may differ between patients taking the same dose depending on the activity of cytochrome B450 leading to significant inter-patient variation.
Dose: PO (with azathioprine): 0.2 mg/kg/day divided q12hr, PO (with MMF/IL-2 receptor antagonist): 0.1 mg/kg/day divided q12hr, IV: 0.03-0.05 mg/kg/day IV by continuous infusion.
Therapeutic window: Narrow, 5 to 15µg/L may be more appropriate.
Recommended to be taken on empty stomach either 1 h before or 2 hours after meals.
MMF:
Mechanism of Action: Acts as non-competitive, selective, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), Inhibits T- and B-cell proliferation, as well as antibody production. Is a Pro-Drug and it’s active compound mycophenolic acid(MPA).
Forms: CELLCEPT (mycophenolate mofetil MMF) and MYOFORTIC (mycophenolic acid MPA).
Dose: Mycophenolate mofetil (MMF): 1 g PO/IV q12hr, Mycophenolic acid (MPA): 720 mg PO q12hr. Cyclosporinedecrease level of MMF, so the recommended dose of MMF when used with cyclosporine is 2 gm, while when used with tacrolimus the dose can be reduced to 1 gm daily.
Can be administered with or without food but in in relation to meals to improve GI tolerability.
Azathioprine:
Mechanism of Action: Purine antimetabolite, converted to 6-MP (pro-drug); may inhibit synthesis of DNA, RNA, and proteins; interferes with cellular metabolism; may inhibit mitosis.
Bioavailability: Well absorbed orally, Peak plasma time: PO 1-2 hr, Peak plasma concentration: <1 mcg/mL.
Distribution: Protein bound: 30%.
Metabolism: Metabolized in liver, Metabolites: 6-MP and 6-thiouric acid.
Elimination: Half-life of parent drug is 12 min but for active metabolite 6-MP is 0.7-3 hours. Slightly prolonged in end-stage renal disease. It’s partially dialyzable and excreted via urine (primarily as metabolites).
Dose: 3-5 mg/kg/day IV/PO initially on day of transplant then maintenance dose of 1-3 mg/kg/day IV/PO.
Allopurinol should be used with great caution with azathioprine because AZA is metabolized by xanthine oxidase and potentiate myelo-suppression.
Can be administered with or without food.
References:
Xu F, Chen ZL, Jin WJ, Xie QD, Shi XH. Ideal therapeutic range of cyclosporine in whole blood in kidney-transplanted patients. Int J Clin Pharmacol Res. 1993;13(4):221-4. PMID: 8150548.
Up-to-date.
Ahmed Omran
3 years ago
Bioavailability refers to the exact level of drug available in circulation for intended effects on target receptors after passing through different barriers . It can be affected by intrinsic or extrinsic factors like physical properties of drugs, dose, formulation and use of other medications or foods .It could be 100 % for IV route while significantly lower in oral route. The time taken-T max to achieve maximum drug concentration and the actual maximum drug concentration will depend on many factors and will be specific for each drug.
Cyclosporine
It can be given through IV and PO. Absorption can be affected by several factors including metabolism by CYP3A..Substances affecting cytochrome can affect Cyclosporine bioavailability. Peak bioavailability can be achieved in 1-8 hours. Almost 50 % can be bound to blood elements like RBC and lymphocytes. It has narrow therapeutic range and close monitoring of drug levels is needed. Significant drug interactions like phenytoin can reduce serum levels while erythromycin can increase the levels.
Tacrolimus.
It is metabolized by cytochrome CYp3A4/5 and can be given by PO and IV routes. The oral formulation is available as 0.5, 01 and 5 mg. It has narrow therapeutic index and bioavailability can be between 5-93%. PO is usually 3-4 times higher than IV dose. In the circulation it bind to proteins and RBCs. Peak level can be achieved in one hour. Metabolism can occur in intestine, liver and kidney. Bioavailability can be affected by multiple factors including diabetes, bowel resection , afro american or non white races.
Azathioprine.
It is an antimetabolite with narrow therapeutic range and bioavailability is around 50-70 % and metabolized in the liver. After PO administration the absorption is quick and peak plasma levels can be seen in 1-2 hours. It is distributed in body fluids except extracellular fluids. Its use should be avoided with allopurinol. Leukopenia can result if used with cotrimoxazole or ACE inhibitors. MMF replaced mostly. MMF
It blocks the proliferation of Band T cells by reversibly inhibiting inosine monophosphate dehydrogenase and rapidly absorbed from gut and 90% is bound to plasma proteins. T max can be achieved in 1.5 hours. Absorption can be affected by antacids and cholestyramine. 93 % is excreted in urine. Its available in 250 mg immediate release form and 500 mg Tabs.
References Handbook of kidney transplantation – Gabriel M Danovitch Uptodate
Shereen Yousef
3 years ago
▪︎What is meant by bioavailability of a drug?
Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action.
▪︎implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
●Cyclosporine
The bioavailability of cyclosporine is variable, ranging from less than 10% to 89% in various populations.
As a result of its lipophilicity, cyclosporine is largely distributed outside of the blood volume once it is absorbed. The volume of distribution ranges from 3 to 5 L/kg.
Cyclosporine is primarily metabolized through the cytochrome P-450 Ill-A enzyme system in the liver, intestine, and kidney.
At least 25 metabolites have been identified; however, the biologic activity and toxicity of these metabolites are considerably less than those of the parent compound. •
Both cyclosporine and its metabolites are excreted primarily in the bile, with only 6% of the dose eliminated itl the urine.
The eliminatioti half-life of the parent compound in the blood is =8 h.
Compared with Sandimmune, Neoral provides increased bioavailability as evident in increased area under the curve (AUC), increased peak blood concetitration and decreased time to peak blood concentration .
Neoral also provides a linear dose response over a wide dosage range, in contrast to Sandimmune.
Half-Life: 8.4 to 27 hours: The time to peak blood cyclosporine concentrations (Tmax) ranges from 1.5 to 2 hours.
Concomitant administration of Neoral with food causes a small (< 20%) but consistent decrease in bioavailability.
Dose usually divide every 12 hours.
●Tacrolimus
Tacrolimus is poorly bioavailable in patients awaiting renal transplantation (mean bioavailability of 14%, range 6–36%) .
This observation explains why tacrolimus is administered intravenously during the immediate postoperative period.
The low bioavailability of tacrolimus could be due to gut metabolism or to poor oral absorption of the drug.
metabolism by CYP3A4 in the liver accounts for an additional 10% of elimination.
Max blood concentration in 1-3 hours, Volume of distribution: 0.68 L/kg.
Primarily eliminated in bile/feces.
12 hour divided doses are usually used.
●MMF
Mycophenolate mofetil is rapidly absorbed in the small intestine, The maximum concentration of its active metabolite, MPA, is attained 60 to 90 minutes following an oral dose.
The volume of distribution of mycophenolate mofetil is 3.6 (±1.5) to 4.0 (±1.2) L/kg.
The protein binding of mycophenolic acid, the metabolite of mycophenolate mofetil, is 97% and it is mainly bound to albumin.
MPAG, the inactive metabolite, is 82% bound to plasma albumin at normal therapeutic concentrations. At elevated MPAG concentrations due to various reasons, including renal impairment, the binding of MPA may be decreased due to competition for binding
The average apparent half-life of mycophenolate mofetil is 17.9 (±6.5) hours after oral administration and 16.6 (±5.8) hours after intravenous administration.
cyclosporin but not tacrolimus decreases entero-hepatic recirculation of MPA , so higher doses of MMF are required with cycloporin.
●Azathioprine
Oral bioavailability 47% (27-80%).,Max blood concentration in 1-2 hours, Primarily eliminated in urine.
Azathioprine is immunosuppression if choice in pregnancy but not with lactation.
Allopurinol should be used with great caution with azathioprine because AZA is metabolized by xanthine oxidase and potentiate myelosuppression.
Reference
Bioavailability and pharmacokinetics of cyclosporine formulations: Neoral® vs Sandimmune® Miles G. Choc.
Marie Antignac, Benoit Barrou, and Saïk Urien
Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients.Br J Clin Pharmacol. 2007 Dec; 64(6): 750–757.
Mohammed Sobair
3 years ago
What is meant by bioavailability of a drug? What is the implementation of
bioavailability on planning the dose of the following immunosuppressive drugs?
Cyclosporine
Tacrolimus
MMF
Azathioprine
Bioavailability:
Refers to the extent a substance or drug becomes completely available to its intended
biological destinations.
For majority purposes, bioavailability is defined as the fraction of the active form of a
drug that reaches systemic circulation unaltered.
The route of administration (ROA) and the dose of a drug have a significant impact on
both the rate and extent of bioavailability.
Concern issue:
Oral drugs, unlike drugs with other ROAs (i.e., IV drugs), must undergo intestinal
absorption and hepatic first-pass metabolism. A myriad of structural and physiological
gastrointestinal (GI) alterations such as GI surgery or chronic inflammatory intestinal
conditions affect this absorption, typically by reducing bioavailability.
Genetic polymorphisms of intestinal transporters that facilitate absorption (i.e., P-
glycoprotein 1) also affect drug bioavailability. Verapamil, a calcium channel blocker that
inhibits P-glycoprotein, has been shown to augment the plasma concentration of
immunosuppressive drugs that utilize P-glycoprotein in their elimination, such as
cyclosporine and tacrolimus, increasing the risk for toxicity.
Bioavailability of a drug will be reduced proportionally to the fraction of the initial dose
converted to inactive metabolites by liver enzymes.Notably, hepatic cytochrome P450
metabolism can significantly alter drug bioavailability. Cytochrome P450 enzymes can be
inhibited or augmented by a concurrent drug, supplement, or food metabolism.
Clinical significance:
Bioavailability of a drug can be influenced by both intrinsic and extrinsic variables.
Intrinsically:
Drug’s required metabolic steps to activation.
The specificity of its target receptors.
The patient’s unique physiology (including phenotypic polymorphisms).
Route of administration of the drug.
And site of drug absorption.
Extrinsic variables affecting drug bioavailability:
Include interactions with concurrent food or substance.
Metabolic processes.
Drug interactions with medications.
MMF:
80.7% (renal transplant patients) .
94% (healthy volunteers).
High-fat meal: ↓Cmax by 40%; AUC is unchanged.
Should be taken on an empty stomach or at a consistent time each day in relation to
meals to improve GI tolerability.
Giving total daily dose in three or four equally divided doses may improve GI tolerability.
MMF Enteric (myfortic).
72% (renal transplant patients.
§ High-fat meal: ↓Cmax by 33%; AUC is unchanged
§ Should be taken on an empty stomach. Cyclosporine non-modified (Sandimmune):
Bioavailability:
Generally poor and unpredictable: § 10 to 89% (renal transplant patients) § <10% (liver transplant patients) Effect of Food on absorption: § High-fat meal: ↓Cmax by 33%; AUC is unchanged § Should be taken on an empty stomach. Cyclosporine modified (microemulsion) (Neoral):
Bioavailability:
23 to 50% better absorbed than non-modified formulation in renal and liver transplant patients, respectively. Effect of Food on absorption: § High-fat meal: ↓Cmax by 33% and ↓AUC by 13% § Should be taken at a consistent time each day in relation to meals.
Tacrolimus immediate-release capsule (Prograf): Bioavailability: 7 to 32%. Effect of Food on absorption § High-fat meal: ↓Cmax by 77% and ↓AUC by 37% § High-carbohydrate meal: ↓Cmax by 65% and ↓AUC by 28% § Should be taken on an empty stomach. § Tacrolimus extended-release capsule (Astagraf XL): Bioavailability: 12-19%. Effect of Food on absorption: § High-fat meal: ↓Cmax by 77% and ↓AUC by 25% § Should be taken preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal. AZA: Hiopurine S-methyltransferase (TPMT) and/or nudix hydrolase 15 (nucleotide
diphosphatase; NUDT15) deficiency. Patients with TPMT and/or NUDT15 deficiency, dosage reduction Administering tablets after meals or in divided doses may decrease adverse GI events. Reduce azathioprine dose to one third to one quarter of the usual dose if used with
allopurinol, and monitor closely for systemic toxicity
CARLOS TADEU LEONIDIO
3 years ago
Bioavailability – refers to the percentage of active drug is found in plasma. Medication format (capsule, tablet, etc.), route of administration (oral, intravenous, topical), and other factors cause bioavailability to vary. So the effectiveness of a drug changes according to how it is administered, thus their serum concentrations must be measured.
Cyclosporine
– Its insoluble in water but soluble in organic solventes and lipids.
– Not significantly dialyzed – so during dialysis treatment not necessary dose adjustment
– Oral bioavailability is governed by absorption, gut metabolism by the isoenzymes of the cytochrome P-4503A (CYP3A) family
– Peak concentratrions in whole blood are attained 1 to 2 hours after oral administration;
– the bioavailability of the orally administred drug is in the range of 30% to 45%. And its increases with time, possibly as a resulto f P-gp inhibitory properties of the drug. As a result, the amount of cyclosporine required to achieve a given blood level tends to fall with time and typically reaches a steady level within 4 to 8 weeks.
Tacrolimus
– Practically insoluble in water, freely soluble in etanol and very soluble in metanol and chloroform
– Not significantly dialyzed – so during dialysis treatment not necessary dose adjustment
– Oral bioavailability is governed by absorption, gut metabolism by the isoenzymes of the cytochrome P-4503A (CYP3A) family. Gastrointestinal absorption is dependente on the presence of food, bile acids and motility.
– Peak concentratrions in whole blood are attained 1 to 2 hours after oral administration. If necessary the drug can be adminstered through a nasogastric tube or sublingually
– Low oral bioavailability – avarage 25%.
– Available in intravenous and capsules. The conversion is safe, but patients should be monitored closely during the process.
– Diarrhea may lead to increased absorption of tacrolimus from the lower GI tract with resultant toxic levels
MMF
– Mycophenolate mofetil is a prodrug to active compound of which is mycophenolic acid (MPA). Orally administered MMF is hydrolyzed to MPA, presystemically and is rapidyd absorbed, producing a peak level in approximately 1 hour.
– The bioavailability of MMF is roughly 90% with 97% of the MPA protein bound to albumin.
–
Azathioprine
– Half of orally administered is absorbed, thus the intravenous dose is equivalente to Half the oral dose;
– The drug is not significantly dialyzed or excreted by the kidney
– Blood levels are not valuable clinically because its effectiveness is not blood-level dependente
– Regular monitoring of hematologic parameters is a importante aspect because marrow suppression.
– dose is 2.5mg/Kg/day when used alone. In triple protocolo or associated with steroids the dose is 1.5mgKg/day.
Nasrin Esfandiar
3 years ago
Bioavailability is the fraction or percent of a drug that enters systemic circulation in comparison with IV administration. So when a drug is administered IV, its bioavailability is 100% (f=1) which is different when it is administer via oral, subcutaneous sublingual, transdermal or rectal routs.
Factors that affect absorption such as concomitant use with food or other drugs or disease that influence liver metabolism or GI functions can alter bioavailability of a drug.
Cyclosporine:
The bioavailability of Neoral (the micro-emulsion formulation) is better and its peak levels (C2) is higher and co has better correlation with drug exposure.
Neural has lesser dependence of bile for absorption and has better GI absorption.
Bioavailability of the orally administered drug is between 30-40 % with conversion dose ratio of 3:1 between oral and IV forms.
Its bioavailability increases over time due to its p-glycoprotein inhibitor activity
So, to reach a steady level with fixed dose 4-8 week is needed.
Its volume of distribution is 3-5 Lit/kg, majority in RBC with high protein binding. Its half-life is between 6-27 h with 25% greater clearance in pre-pubertal ones.
The majority of drug is excreted in the bile and less than 6% in the urine and 0.1 unchanged .
Tacrolimus:
It is not dependent on bile for absorption and oral bioavailability is limited (20%) due to poor absorption, bowel mucosa causing partial metabolism and first-pass hepatic metabolism. The bioavailability of extended release tacrolimus is almost 50% higher than immediate –release.
There are inter and metabolism of CNIs.
There absorption is decreased with a fatty meal. Tacrolimus is taken up by erythrocytes and binds to proteins (albumin and α1-acid glycoprotein).
Their metabolism is through cytochrome p-450 CYP3A in the liver and gut mucosa and drugs that inhibit or induce their activity can increase or decrease their blood levels respectively.
MMF: oral MMF is hydrolyzed to mycophenolic acid and peak in about one hour.
The bioavailability of MMF is rough 90%.
The majority of MPA bound to albumin.
Enteric coated MPA only dissolves in the intestine with neutral PH and peaks after 2-3 hours.
Its AUC increase with time, MPA is glucuronidated to MPAG which has enterohepatic cycling causing a second peak at 6-12 hours.
Its half is about 6-18 hours.
Azathioprine (Imuran): It is an antimetabolite and can be used in pregnancy.
The bioavailability of orally administered azathioprine, comparing to IV dose is about 50%.
As an adjunction therapy with CNI its dose is 1-2 mg/kg
manal jamid
3 years ago
Bioavailability is a key indicator of drug absorption. It represents the administered dose fraction which achieves success in reaching the systemic circulation when administered orally or through any other extravascular dosing route. Cyclosporine. It is a lipophilic molecule, with its bioavailability dependent on food, bile and other interacting factors. Is extensively metabolized in the liver by the cytochrome P450 3A system. Distribution depends on physicochemical, biological carriers such as lipoproteins and erythrocytes in blood. The distribution of metabolites in the body can differ from that of cyclosporine itself. Elimination of the drug is mainly via the bile as metabolites, to lesser extent through the kidney Pharmacokinetic parameters of cyclosporine are highly variable and depend on factors such as age, the physical condition of the patient, type of organ transplant. Renal side effects of cyclosporine are dose-related. The therapeutic range and dosage of cyclosporine are therefore highly dependent on many individual parameters in patients. Dosages of less than 5 mg/kg/day, however, rarely cause renal side effects. Further studies to correlate the clinical pharmacokinetics of metabolites with their activity and adverse effects are needed. Following oral administration, the absorption of cyclosporine is slow and incomplete. Peak concentrations in blood or plasma are reached in 1 to 8 hours after dosing. The bioavailability of cyclosporine ranges from less than 5% to 89% in transplant patients; poor absorption has frequently been observed in liver and kidney transplant patients and in bone marrow recipients. Factors that affect the oral absorption of cyclosporine include the elapsed time after surgery, the dose administered, gastrointestinal dysfunction, external bile drainage, liver disease, and food.
Tacrolimus is Tacrolimus is primarily metabolized by the cytochrome P450 system of liver enzymes, and there are many substances that interact with this system and induce or inhibit the system’s metabolic activity. Interactions include that with grapefruit which increases tacrolimus plasma concentrations., the most commonlyreported interactions include interactions with anti-microbial drugs. Macrolide antibiotics including erythromycin and clarithromycin, as well as several of the newer classes of antifungals, especially of the azole class (fluconazole, voriconazole), increase tacrolimus levels by competing for cytochrome enzymes. The half-life is 12 hours and the total body clearance based on blood concentration is approximately 0.06 L/h/kg. The elimination of tacrolimus is decreased in the presence of liver impairment and in the presence of several drugs. Various factors that contribute to the large inter- and interindividual variability in the pharmacokinetics of tacrolimus are reviewed here. Because of this variability, the narrow therapeutic index of tacrolimus, and the potential for several drug interactions, monitoring of tacrolimus blood concentrations is useful for optimization of therapy and dosage regimen design. Oral tacrolimus is slowly absorbed in the gastrointestinal tract, with a total bioavailability of 20 to 25% (but with variations from 5 to 67%) and highest blood plasma concentrations reached after one to three hours. Taking the drug together with a meal, especially one rich in fat, slows down resorption and reduces bioavailability. MMF itself is not pharmacologically active: once MMF is absorbed, it is metabolized to mycophenolic acid (MPA), the major active metabolite. When cyclosporine is coadministered with MMF in transplant patients, the plasma concentration or exposure of MPA is reduced [and MPAG concentration increased compared with patients receiving MMF plus tacrolimus or MMF plus sirolimus The differences in MPA concentration between these regimens have been attributed to the pharmacokinetic interaction between MPA and cyclosporine. oral bioavailability: 94%. · Max blood concentration in 1 ½ hour, second peak 6-12 hours later due to enterohepatic circulation · Volume of distribution: 0.71 L/kg. Primarily eliminated in urine (93%). · absorbed only in the small intestine, with peak concentration after 2-3 hours. Azathioprine: Oral bioavailability 47% (27-80%). • Max blood concentration in 1-2 hours. • Dose:2mg/kg as a single dose not divided • Volume of distribution: 0.1 – 1.7 L/kg. • Primarily eliminated in urine. • Azathioprine is safe in pregnancy as The fetus does not have the liver enzyme to do that BUT after birth, his liver becomes mature and able to metabolize it so its better to stop AZA after delivery if she tends to breastfeed. • Allopurinol should be used with great caution with azathioprine because AZA is metabolized by xanthine oxidase and potentiate myelosuppression. • Genetic polymorphisms of certain enzymes play an important role in the metabolism of azathioprine, namely thiopurine S-methyltransferase (TPMT) and nucleoside triphosphate diphosphatase (NUD15). The deficiency of TPMT can cause the accumulation of 6-thioguanine nucleotides and 6-methylmercaptopurine, leading to hematological toxicity and hepatotoxicity.
amiri elaf
3 years ago
# What is meant by bioavailability of a drug?
What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
# Cyclosporine
# Tacrolimus
# MMF
# Azathioprine
** Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action.
Bioavailability of a drug is largely determined by the properties of the dosage form, which depend partly on its design and manufacture.
** CYCLOSPORINE:
# The absorption of cyclosporine occurs mainly in the intestine, and is highly variable
# Bioavailability of 30% sometimes occurring 1-8 hours after administration with a second peak observed in certain patients.
# T- max :higher Tmax and a 59% higher Cmax with a 29 % higher bioavailability
# Volume of distribution:
The distribution in the blood consists of 33%-47% in plasma, 4%-9% in the lymphocytes, 5%-12% in the granulocytes, and 41%-58% in the erythrocytes
# Protein binding: About 50% of the administered dose is taken up by erythrocytes while about 34% is bound to lipoproteins,Prescribing information for Sandimmune states that 90% is mainly bound to lipoproteins.
#Metabolism: Cyclosporine is metabolized in the intestine and the liver by CYP450 enzymes, predominantly CYP3A4 with contributions from CYP3A5. Cyclosporine undergoes several metabolic pathways and about 25 different metabolites have been
identified.
# Elimination:
primarily biliary with only 3-6% excreted in the urine while 90% in the bile.1% unchanged
# The half life: of cyclosporine is biphasic and very variable on different conditions last 19 hours a range between (10 – 27 ) hours
# Common adverse effects are hypertrichosis, gingival hyperplasia, hyperlipidemia and nephrotoxicity,nausea, flushing, tremor, vertigo and vomiting, anorexia and a feeling of increased body girth.
** TACROLIMUS:
#Resorption (poor) throughout the gastrointestinal tract.
# The bioavailability is : 20 – 25%
# T max is : 1 – 3 hours (capsules and granules or 6 hours(tablets)
# Volume of distribution is : 0.68 l/kg
# Protein bound fraction is more than 99%
Metabolsim : CYP3A4- mediated metabolism in liver and intestinal epithelium
# Elimination is : 95 % with faeces
# Elimination half-life : 12- 15 hours
# Common adverse effects: Hypertension
diarrhoea, hyperglycaemia, anaemia, headache, tremor, insomnia
** MMF
# Rapidly converted to mycophenolic acid by plasma esterase, resorption throughout gastrointestinal tract.
# The bioavailability is : 94%
# T max is : 1.5 hour and a second peak between 6 – 12 hours owing to enterohepatic circulation.
# Volume of distribution is : 0.71 l/kg
# Protein bound fraction is 97%
Metabolsim : conversion to inactive glucuronide metabolite in liver
# Elimination is : 93% in urine, the remaining with faeces
# Elimination half-life : 12- 18 hours
# Common adverse effects:
diarrhoea, nausea, vomiting, leukopenia, anaemia, increase in blood creatinine, CMV viraemia, UTI, RTI and hepatitis
** AZATHIOPRINE
# Highly variable resorption throughout gastrointestinal tract.
The bioavailability is : 47%(27-80%)
# T max is : 1-2 hours
# Volume of distribution is : 0.1- 1.7 l/kg
# Protein bound fraction is 20 – 30 %
Metabolsim : rapid conversion in to 6 – mercaptopurine(a process that is partially dependent on TPMT)
# Elimination is : mainly with urine ,(as inactive thio-uricacid) small fraction eliminated with faeces
# Elimination half-life : 60 – 120 minutes(after conversion to 6 – mercaptopurine)
# Common adverse effects:
Nausea, vomiting, hepatic dysfunction, infection(viral, fungal, bacterial) and anorexia.
nawaf yehia
3 years ago
In pharmacology, bioavailability ( f ) is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100
order to determine absolute bioavailability of a drug, a pharmacokinetic study must be done to obtain a plasma drug concentration vs time plot for the drug after both intravenous (iv) and non-intravenous( i.e., oral) administration. The absolute bioavailability is the dose-corrected area under curve (AUC) non-intravenous divided by AUC intravenous.
f = 100 *( AUC po * D iv / AUC iv * D po )
f : bioavailability
D dose
Therefore, a drug given by the intravenous route will have an absolute bioavailability of 100% (f = 1), whereas drugs given by other routes usually have an absolute bioavailability of less than one
Cyclosporin
Tthe bioavailability of the orally administered drug is in the range of 30% to 45%. Conversion between the oral and intravenous forms of the drug perioperatively requires a 3:1 dose ratio and is administered twice daily as 4-hour infusions .
foods and drugs can affect its bioavailability.
tacrolimus
Despite its relatively poor bioavailability, it is rarely necessary to use the intravenous
formulation. If necessary, the drug can be administered through a nasogastric tube or sublingually. Intravenous dosing is approximately one-third of the total daily dose required by the oral route and is administered via a 24-hour continuous infusion. Sublingual dosing is more variable, but is usually one-half that required by the oral route.
With the immediate-release dosage forms, it is absorbed primarily from the small intestine, and its oral bioavailability is about 25%,with large interpatient and intrapatient variability .
MMF
both MMf ( CellCept ) and EC MPA ( Myfortic ) have Mycophnolic acid MPA as the active compound
The bioavailability of MMF is roughly 90%, with 97% of the MPA protein bound to albumin . the AUC of MPA increases with time; the same doses when used early postoperatively can produce much higher concentrations several months later. Patients should be continuously for adverse side effects and periodically be evaluated for an
MPA dose reduction, if clinically appropriate
Azathioprine
About half of orally administered azathioprine is absorbed; thus, the intravenous dose is equivalent to half the oral dose .
Blood levels are not valuable clinically because its effectiveness is not blood-level dependent.
handbook of kidner transplantation , 6th edition .
Ramy Elshahat
3 years ago
What is meant by the bioavailability of a drug? Bioavailability means the proportion that reaches the peripheral circulation active and unchanged after intake.
Oral Bioavailability = (AUCoral/ AUCintravenous) x 100% Factors affecting bioavailability 1. GIT absorption 2. Rate of transit 3. GIT excretion and liver elimination What is the implementation of bioavailability in planning the dose of the following immunosuppressive drugs? Cyclosporine: • Oral bioavailability: 30-45%, • first-pass metabolism by CYP3A4 in the liver so any drug inhibits CYP3A4 (increase the cyclosporin level and vice versa) • The absorption from the gastrointestinal tract is also influenced by the activity of P-glycoprotein (P-gp) in enterocytes which has an inhibitory effect (responsible for efflux of cyclosporine in gut lumen) • steady state achieved in 4-8 weeks. • Less dependence on bile for absorption with the microemulsion form but Food decreases absorption. • Max blood concentration in 2 hours, Volume of distribution: 3-5 L/kg. • Primarily eliminated in bile/feces, only 6% in urine(no change in dose-related to advanced kidney disease). • Starting Dose has very wide from center to another usually 4-8mg/kg >>our center experience is to start with high dose(6mg/kg if the patient didn’t receive induction therapy), follow up is by trough level which also center-based and change regarding the duration of transplantation Tacrolimus: · Oral bioavailability: 25%. · Dose: wide range from 0.1-0.2 >> our center usually use a higher dose in thin patients, pediatrics, and patients who didn’t receive any kind of induction · first-pass metabolism by CYP3A4 in the liver accounts for an additional 10% of elimination. · The extent of absorption of tacrolimus from the gastrointestinal tract is also influenced by the activity of P-glycoprotein (P-gp) in enterocytes., which explains the high levels of tacrolimus during diarrheal episodes · Max blood concentration in 1-3 hours, Volume of distribution: 0.68 L/kg. Primarily eliminated in bile/feces. · fast metabolizer: drug level/ the dose of tacrolimus used was < 1, and need higher doses of tacrolimus and is at higher risk of rejection. MMF(Cellcept): · oral bioavailability: 94%. · Max blood concentration in 1 ½ hour, second peak 6-12 hours later due to enterohepatic circulation (that’s why to trough level doesn’t correlate with the AUC) · Volume of distribution: 0.71 L/kg. Primarily eliminated in urine (93%). Enteric-coated MMF (MPA >>Myfortic) · absorbed only in the small intestine, with peak concentration after 2-3 hours. · Dosing: in body weight below 40kg>23mg/kg/12h, above 40kg >>2gm/day independent of body weight and also dose change with the duration of transplantation and according to CBC · Monitoring of AUC is not routinely done but some time is needed( if the patient is presented with recurrent infections and leucopenia after exclusion of CMV hematological manifestations) · MMF inhibit Donovo pathway only for purine synthesis in lymphocytes And T and B lymphocytes(other cells have salvage pathway) solely on this pathway for the production of guanosine nucleotides Azathioprine: Oral bioavailability 47% (27-80%). • Max blood concentration in 1-2 hours. • Dose:2mg/kg as a single dose not divided • Volume of distribution: 0.1 – 1.7 L/kg. • Primarily eliminated in urine. • Azathioprine is safe in pregnancy as The fetus does not have the liver enzyme to do that BUT after birth, his liver becomes mature and able to metabolize it so its better to stop AZA after delivery if she tends to breastfeed. • Allopurinol should be used with great caution with azathioprine because AZA is metabolized by xanthine oxidase and potentiate myelosuppression. • Genetic polymorphisms of certain enzymes play an important role in the metabolism of azathioprine, namely thiopurine S-methyltransferase (TPMT) and nucleoside triphosphate diphosphatase (NUD15). The deficiency of TPMT can cause the accumulation of 6-thioguanine nucleotides and 6-methylmercaptopurine, leading to hematological toxicity and hepatotoxicity.
Zahid Nabi
3 years ago
Bioavailability refers to the extent a substance or drug becomes completely available to its intended biological destination(s).
Bioavailability is expressed as the percentage of the total drug dose administered that reaches the circulation. For a drug taken orally, the ‘first-pass effect’ of hepatic metabolism reduces bioavailability. The bioavailability calculations include both free and bound forms of the drug. A systemic drug with a relatively low bioavailability is acyclovir; the prodrug for acyclovir, valacyclovir, has at least three times greater bioavailability. At the other end of the spectrum are the fluoroquinolones, for which oral absorption (and resultant bioavailability) is so complete that the oral and intravenous doses for many members of this drug group are identical.
1 Ciclosporin
Oral bioavailability: 30-45% . reach max concentration in 2 hours . Absorption decrease with meal . excreted mainly in feaces and small amount by kidneys. Drugs which inhibit the P glycoprotein will increase the systemic concentration of the CYC. For example diltiazem and verapamil inhibit the p Efflux glycoprotein and increase the levels of CYC in the blood. Drugs like Rifampicin can induce the P efflux glycoprotein and decrease the bio availability of the drug.
I think while prescribing we should keep in mind the fact that certain factors can decrease the bioavailability like pregnancy so dose is adjusted accordingly.
2.Tacrolimus
Oral bioavailability is highly variable and ranges from 5 to 93%. No dependence on bile for absorption. Max blood concentration in 1-3 hours, Food decreases absorption, It is metabolized by the enzyme CYP3A5. Pharmacogenetics have divided patients into poor and extensive metabolizers based on CYP3A5 genotyoe analysis. It is primarily eliminated in bile/ faeces. Diarrhea may lead to increased absorption from lower GI tract, causing toxic levels.
3.MMF
It is a prodrug with oral bioavailability: 94%. Max blood concentration in 1 ½ hours, second peak 6-12 hours later due to enterohepatic circulation. MMF is mainly eliminated in urine (93%). Enteric coated MMF absorbed only in small intestine, with peak concentration after 2-3 hours.If taken with food the bioavailability will decrease so better to be taken empty stomach though patients find it but difficult.
4. Azathiprine
The bioavailability of AzA is 16-50% with predominant hepatic metabolism, elimination half life 1-2 hours. Mainly eliminated in urine. It is administered after meals to avoid GI side effects.
While prescribing these immunosuppressive drugs we should keep in mind the factors affecting bioavailability
Is the drug given IV or oral
With food or empty stomach
Any associated drug affecting bioavailability
Age of patient
Effect of pregnancy on bioavailability
Effect of p glycoprotein
Enzyme CYP3A5
Inter patient variability
Any associated disease like liver disease
Etc
Balaji Kirushnan
3 years ago
Bioavailability of a drug means the proportion of the drug which reaches the peripheral circulation and site of action unchanged after getting absorbed.
Bioavailability of an oral drug is calculated by comparing the AUC of the unmetabolized drug after intravenous and oral administration.
Bioavailability depends on the physio chemical barriers in the gastro intestinal mucosa, gastro intestinal transit rate and it depends on the pre systemic/first pass metabolism of drugs like MMF
Cyclosporine: Oral bioavailability: 30-45%, increases with time due to inhibitory effect on P glycoprotein (responsible for efflux of cyclosporine in gut lumen), steady state achieved in 4-8 weeks. Original sandiimmune form took a lot of time to get absorbed and depends on bile for the absorption. The microemulsion form has better and consistent absorption better than the sanimmune form. Max blood concentration in 2 hours, Volume of distribution: 3-5 L/kg. Food decreases absorption. Drugs which inhibit the P glycoprotein efflux pump will increase the systemic concentration of the CYC. For example diltiazem and verapamil inhibit the p Efflux glycoprotein and increase the levels of CYC in the blood. Drugs like Rifampicin can induce the P efflux glycoprotein and decrease the bio availability of the drug. It is primarily eliminated in bile/ faeces, only 6% in urine.
Tacrolimus: Oral bioavailability is highly variable and ranges from 5 to 93%. No dependence on bile for absorption. Max blood concentration in 1-3 hours, Volume of distribution: 0.68 L/kg. Food decreases absorption, hence better to give empty stomach. It is metabolized by the enzyme CYP3A5. Pharmacogenetics have divided patients into poor and extensive metabolizers based on CYP3A5 genotyoe analysis. It is primarily eliminated in bile/ faeces. Diarrhea may lead to increased absorption from lower GI tract, causing toxic levels.
MMF: It is a prodrug with oral bioavailability: 94%. Max blood concentration in 1 ½ hours, second peak 6-12 hours later due to enterohepatic circulation. Volume of distribution: 0.71 L/kg. Primarily eliminated in urine (93%). Enteric coated MMF absorbed only in small intestine, with peak concentration after 2-3 hours. AUC of mycophenolic acid increases over time. The bioavailability of the drug gets reduced with high fat diet, hence better to take empty stomach to increase absorption. It can be given with food at specific times, if patient has GI effects.
Azathioprine: Oral bioavailability: 47% (27-80%). Max blood concentration in 1-2 hours. Volume of distribution: 0.1 – 1.7 L/kg. Primarily eliminated in urine. It is administered after meals to avoid GI side effects.
Although many of the drugs are to be recommended to be given in empty stomach, many patients do not tolerate it when taken before food. To be consistent in the drug and achieving their drug levels, we can ensure that they are taken in a particular time of the day.
Batool Butt
3 years ago
Bioavailability is percentage of drug that reaches systemic circulation unchanged form
It includes both the extent and rate of drug absorption.
The extent of drug absorption represents the fraction of the administered amount of drug that reach peripheral circulation in its active form. Bioavailability of an oral drug is calculated by comparing the AUC (area under the curve).The oral bioavailability of a drug can be defined as:
Oral Bioavailability = (AUCoral/ AUCintravenous) x 100%
Bioavailability of drugs administered orally is determined physiochemical barriers to absorption as gastrointestinal mucus membranes, pre systemic metabolism and/or excretion by gut or liver. What is the implementation of bioavailability of planning the dose of the following immunosuppressive drugs?
Cyclosporine :Bioavailability(oral)is 30-68% with half life of 5-18 hours. The original formulation of cyclosporine, the oil-based Sandimmune, has largely been replaced by the microemulsion formulation, (Neoral) which is better than that of Sandimmune, and have less variability in cyclosporine pharmacokinetics and also less dependent on bile for absorption. Conversion between the oral and intravenous forms of the drug peri-operatively require a 3:1 dose ratio and is administered twice daily as 4-hour infusions.
The dose is 3-5mg/Kg twice daily. Primarily eliminated in bile/ faeces, only 6% in the urine. Food decreases absorption, hence better to give an empty stomach. Primarily eliminated in bile/ feces. Diarrhea may lead to increased absorption from the lower GI tract, causing toxic levels. Tacrolimus: Bioavailability is 20-25% with half -life of 12-15 hours.The dose is 0.15-0.3mg/Kg twice daily. Food decreases absorption, hence better to give an empty stomach. Primarily eliminated in bile/ feces. Diarrhea may lead to increased absorption from the lower GI tract, causing toxic levels
Tacrolimus and cyclosporine are metabolized through CYP3A enzyme system
Liver dysfunction prolongs the half-life of both drugs. Food decreases CNI absorption
12 -hour trough level is used for monitoring drug level, dose changes are reflected in 2-3 days.
Ciclosporin trough level-(200-300ng/ml) in the first 03 months after transplantation
-50-150 ng/ml for subsequent months
Tacrolimus trough level- 7-10 ng/ml in 01 to 03 months after transplantation
3-7ng/ml for subsequent months MMF–Prodrug converted to an active metabolite (mycophenolic acid), oral bioavailability is 94%.Max blood concentration in 1 ½ hour, second peak 6-12 hours later due to enterohepatic circulation. Primarily eliminated in urine (93%).The dose of Cellcept is 1gm twice daily.The dose of Myfortic is 720mg twice daily. The bioavailability of the drug gets reduced with high-fat diet, hence better to take an empty stomach to increase absorption. Cyclosporine decreases the level of MMF, so the recommended dose of MMF when used with cyclosporine is 2 gm, while when used with tacrolimus the dose can be reduced to 1 gm daily Azathioprine: Analogue of 6 mercaptopurine and bioavailability is 16-50% with predominant hepatic metabolism,elimination half life 1-2 hours. Primarily eliminated in urine. It is administered after meals to avoid GI side effects.The dose is 3-5 mg/kg/day IV/PO initially on the day of transplant than a dose of 1-3 mg/kg/day IV/PO. Deficiency of enzyme TPMT can cause accumulation of 6-methylmercaptopurine leading to hepatotoxicity. Xanthine oxidase inhibitors should be avoided with azathioprine as increase the risk of accumulation of 6-mercaptopurine with consequent serious toxicity. REFERENCES: 1-Srinivas TR, Meier-Kriesche HU, Kaplan B. Pharmacokinetic principles of immunosuppressive drugs. Am J Transplant. 2005 Feb;5(2):207-17. 2- Danovitch G.M handbook of kidney transplantation sixth edition
dalia
3 years ago
Bioavailability is the proportion of an administered dose of a drug that reaches the systemic circulation as intact drug . As an i.v. dose is injected directly into the systemic circulation, the bioavailability of an i.v. dose is by definition 100 percent
Cyclosporine: Oral bioavailability: 30-45% . reach max concentration in 2 hours . Absorption decrease with meal . excreted mainly on fesses and small amount by kidneys
· Tacrolimus: Oral bioavailability: 25%. reach max concentration in circulation 1-3 hours, . absorption decrease with meals, so better to give it in empty stomach.excreted on faeces. Diarrhea may lead to increased TAC blood level .
· MMF: oral bioavailability: 94% .excreted mainly in urine. Enteric coated MMF absorbed only in small intestine, with peak concentration after 2-3 hours .better In empty stomach .
· Azathioprine: Oral bioavailability: 47% .reach max concentration in circulation in 1-2 hours. Excreted mainly in urine
Heba Wagdy
3 years ago
Bioavailability is percentage of drug that reach systemic circulation unchanged form
It includes both the extent and rate of drug absorption.
The extent of drug absorption represent the fraction of the administered amount of drug that reach peripheral circulation in its active form.
Bioavailability of drugs administered orally is determined by physiochemical barriers to absorption as gastrointestinal mucus membranes, pre systemic metabolism and/or excretion by gut or liver.
Cyclosporine
Bioavailability is 30-68% with half life of 5-18 hours
The dose is 3-5mg/Kg twice daily
Tacrolimus
Bioavailability is 20-25% with half life of 12-15 hours
The dose is 0.15-0.3mg/Kg twice daily Tacrolimus and cyclosporine are metabolized through CYP3A enzyme system
Suboptimal bioavailability of is due to poor intestinal absorption, partial enzymatic metabolism in gastrointestinal mucosa and first pass hepatic metabolism.
Liver dysfunction prolong the half life of both drugs
12 hour trough level is used for monitoring drug level, dose changes are reflected in 2-3 days.
MMF
Prodrug converted to active metabolite (mycophenolic acid), oral bioavailability is 94% with half life of 17.9+/-6.5 hours
The metabolism is hepatic and enter enterohepatic circulation
The dose of Cellcept is 1gm twice daily
The dose of Myfortic is 720mg twice daily
Azathioprine
Analogue of 6 mercaptopurine
Bioavailability is 16-50% with predominant hepatic metabolism
elimination half life 1-2 hours
the dose is 1-2mg/kg when used as adjunctive with CNI
Deficiency of enzyme TPMT can cause accumulation of 6-methylmercaptopurine leading to hepatotoxicity
Xanthine oxidase inhibitors should be avoided with azathioprine as increase the risk of accumulation of 6-mercaptopurine with consequent serious toxicity.
Srinivas TR, Meier‐Kriesche HU, Kaplan B. Pharmacokinetic principles of immunosuppressive drugs. American Journal of transplantation. 2005 Feb;5(2):207-17.
Kant S, Kronbichler A, Geetha D. Principles of Immunosuppression in the Management of Kidney Disease: Core Curriculum 2022. American Journal of Kidney Diseases. 2022 Apr 16.
Danovitch GM, editor. Handbook of kidney transplantation. Lippincott Williams & Wilkins; 2009 Oct 1.
Dalia Ali
3 years ago
Bioavailability
Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action.
Bioavailability of a drug is largely determined by the properties of the dosage form, which depend partly on its design and manufacture. Differences in bioavailability among formulations of a given drug can have clinical significance; thus, knowing whether drug formulations are equivalent is essential.
Cyclosporine and Tacrolimus
Absorption —
Cyclosporine and tacrolimus are absorbed in the small intestine, and peak blood concentrations occur after one to eight hours. The oral bioavailability is limited for both drugs (roughly 20 percent for tacrolimus) as a result of poor absorption, partial metabolism by enzymes in the bowel mucosa, and first-pass hepatic metabolism
modified formulations of cyclosporine lead to higher area under the time concentration curve (AUC) than the nonmodified preparations.
oral bioavailability of extended-release tacrolimus tablets was approximately 50 percent higher as compared with tacrolimus immediate-release at steady state
Both extended-release tacrolimus products exhibit chronopharmacokinetic effects; evening administration, compared with morning dosing, results in a 15 percent lower AUC for extended-release tacrolimus tablets and a 35 percent lower AUC for extended-release tacrolimus capsules Thus, both products should be taken consistently every morning.
The absorption and metabolism of calcineurin inhibitors may vary with race and ethnicity.
the mean tacrolimus exposure after a single 5 mg oral dose in healthy Hispanic and African-American individuals was 18 and 39 percent less, respectively, than in White individuals
Similar results have been seen with the extended-release products
Such variation may be related to differences in the frequency of polymorphisms in the CYP3A5 gene among African-American, Hispanic, and White transplant recipients
The absorption of cyclosporine, but not tacrolimus, is dependent upon bile salts. Thus, cyclosporine modified or tacrolimus may be preferable in patients with biliary diversion or cholestasis. Cyclosporine modified absorption is decreased modestly when ingested with a fatty meal
Similarly, tacrolimus absorption is decreased if administered after a fatty meal and should be taken on an empty stomach, if possible
Distribution —
Cyclosporine and tacrolimus are lipophilic and undergo extensive body distribution. In the blood, most of the absorbed amount of each drug is taken up by erythrocytes. In the plasma, cyclosporine binds mainly to lipoproteins, whereas tacrolimus binds to proteins, primarily albumin and alpha-1-acid glycoprotein.
Metabolism —
Cyclosporine and tacrolimus are extensively metabolized by cytochrome P-450 CYP3A enzymes in the liver. There is also some metabolism in the gut mucosa. The most active cyclosporine metabolites have only 10 to 20 percent of the drug’s immunosuppressive activity. By comparison, one of the metabolites of tacrolimus possesses equal immunosuppressive potency to the parent drug.
Elimination —
Cyclosporine and tacrolimus are excreted in the bile. The elimination half-life can vary significantly among patients, is approximately 19 hours for cyclosporine modified and 12 hours for immediate-release tacrolimus.
Food and drug interactions
Grapefruit or grapefruit juice can result in an increase in systemic exposure to cyclosporine or tacrolimus
Drugs
Macrolides
macrolides for respiratory tract infections: acute cyclosporine/tacrolimus toxicity may occur
Azathioprine
Azathioprine (Imuran) is an antimetabolite, an imidazole derivative of 6-mercaptopurine. It has been used in clinical transplantation for nearly 50 years. When cyclosporine was introduced, the role of azathioprine was largely relegated to that of an adjunctive agent, and with the introduction of MMF, its use has been discontinued in many programs. It can still be useful in certain circumstances and can be a valuable component of a low-cost immunosuppressive regimen
Mechanism of Action.
Azathioprine is a purine analogue that is incorporated into cellular deoxyribonucleic acid (DNA), where it inhibits purine nucleotide synthesis and interferes with the synthesis and metabolism of ribonucleic acid (RNA)
It is ineffective in the therapy of rejection episodes.
About half of orally administered azathioprine is absorbed; thus, the intravenous dose is equivalent to half the oral dose. Blood levels are not valuable clinically because its effectiveness is not blood-level dependent. The drug is not significantly dialyzed or excreted by the kidney. Dose reduction is often practiced during kidney dysfunction, although it may not be necessary. When used as the primary immunosuppressant, the daily oral dose is 2 to 3 mg/kg. When used as adjunctive therapy with a CNI, the dose is 1 to 2 mg/kg.
The azathioprine dose is usually reduced or stopped during episodes of significant hepatic dysfunction.
Mycophenolic Acid
Mechanism of Action.
MPA is a reversible inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH). IMPDH is a critical, rate-limiting enzyme in the so-called de novosynthesis of purines and catalyzes the formation of guanosine nucleotides from inosine.
Absorption and Distribution
Absorption and Distribution The pharmacokinetics of MPA is complex. Orally administered MMF is hydrolyzed to MPA presystemically and is rapidly absorbed, producing a peak level in approximately 1 hour. The bioavailability of MMF is roughly 90%, with 97% of the MPA protein bound to albumin. Orally administered ecMPA exhibits different absorption kinetics owing to the formulation; the tablets only dissolve under neutral pH conditions, and thus absorption only occurs in the intestine. It has a peak concentration after approximately 2 to 3 hours.
Cyclosporine lowers MPA concentrations by decreasing its enterohepatic recycling via OATP1B1 inhibition. Trough levels of MPA increase when cyclosporine administration is discontinued. This interaction is not seen with everolimus, sirolimus, or tacrolimus, and the maintenance dosage of MMF, when used with standard doses and blood levels of these drugs, is typically 500 to 750 mg twice daily. MMF should not be administered simultaneously with antacids, cholestyramine, sevelamer, or oral ferrous sulfate, all of which decrease intestinal absorption. MMF, as opposed to azathioprine, can be administered with allopurinol without dose adjustment. Potential interactions may occur when MMF is administered concomitantly with acyclovir and ganciclovir, and it is wise to discontinue MMF when there is evidence of systemic herpes infection necessitating use of high dosages of the antiviral drugs.
Reference
1- Up to date
2- Gabriel M. Danovitch, MD. Handbook of Kidney Transplantation. SIXTH EDITION.
Theepa Mariamutu
3 years ago
Azathioprine
Dose, metabolism and Monitoring
-dose : 2.5mg/kg/day
-Collaborative Transplant study – patient who receiving steroids and Aza- doses greater than 1.5mg/kg/day were associated with greater graft function
-when administrated with CNI and steroid -1.5mg/kg/day (100mg/day) are appropriate
-Xanthine oxidase important in catabolism of mercaptopurine: allopurinol used with AZA need 25% Aza dose reduction – to avoid bone marrow suppression
Side effects
-bone marrow suppression- leukopenia, anaemia and thrombocytopenia
-megaloblastic anaemia due to hepatitis
-mercaptopurine metabolites intercalated into DNA of the skin increase sensitivity to UV light – risk for squamous cell ca but not basal cell ca
Mycophenolates
Dosing
-common dose – 1g BD
-IV same dose but infuse over 2 hours
Absorption
-orally delivered is rapid and almost completely absorbed
-hydrolysed to MPA
-absorption assessed by AUC- not significantly altered by food but Cmax is 40% lower in simultaneously fed renal Tx patient
-Tmax is less than 1 hour – independent of liver and renal function
-Tmax is delayed post Tx (1.31 SD 0.76 hours) and in DM patients
-MMf to MPA 94%bioavailability
-dose range of 100mg-3000mg is safe (MPA AUC for 24 H )
-EC-MPA – does not release MPA under acidic (pH<5) in the stomach but rapidly absorbed in intestine
-so T max is 1.5-2.75 h – delayed compared to MMF
-GI absorption is 93% and bioavailability of MPA after administration
-EC-MPS -720mg similar to 1000mg MMF
Metabolism and clearance
-rapidly metabolised to an inactive glucoronide (MPAG) via UGT1 in the GI, liver and some at kidney
-elimination – 17.9H ( healthy individuals)
-37%of patient shows secondary peak in plasma MPA concentration representing enterohepatic circulations
-MPAG binds to albumin (97%) but reversible
-estimate free MPA in ultrafiltrate samples did not show any benefit over total MPA level in predicting therapeutic vs adverse events
Blood monitoring
-measured in plasma by high performance liquid chromatography
-enzyme multiplier immunoassay technique (EMIT) -15-20% higher results because of antibody reagent cross reacts with acyl-MPAG metabolite
-EMIT -preferable and most widely utilised
-gold standard -sampling of blood over 12 hr period, with calculation of AUC conc-time exposure
-MPA AUC- calculated full ( 8 samples in 12H) or 2-5 samples over 4 hours.
-12H predose C0 MPA level are convenient
-MPA exposure increases by 30-50% after stable dose 1 week post RTx
-MPA exposure/dose relationship may differ in the settings of KTx, liver Tx, Small Bowel Tx, BM Tx
-due to differences in hepatic/renal function , concurrent drug administration, presence of diarrhoea-pharmacokinetic variability of MMF has been stated; not to gender and ethnicity
– peripheral blood lymphocyte from patients on MMf demonstrated reduced response to stimulation assay and diminished antibody production
-IMPDH assay -technically demanding and difficult to reproduce
-IMPDH activity level fluctuations made the assay difficult in predicting either the efficacy or toxicity of MMF in Tx
Therapeutic drug monitoring – MPA
-marked variabilities in pharmacokinetics provides a rationale to monitor
APOMYGRE
-all patients on CSA and steroids – randomised to receive fixed dose or CC MMF.
– measure the MMF level by limited sampling AUC and dose adjustment by Bayesian algorithm
-significant benefit in CC group with less rejection at 12 months
-MMF dose were higher in CC group with similar adverse events
FDCC study
-901 european KT recipients – randomised to CC (AUC 45mg/hr) or standard dose fixing
-two groups similar in rejections
-there is strong relationship between MPA exposure and rejection (37% had AUC 1.6 with reduced rejection rate
Recent consensus
-AUC target 30-60mg/hr/L
-recommended C0 >1.3mg/L with CSA and C0 >1.9mg/L with tacrolimus
FDCC and Opticept- 2g daily dose is adequate early MMF exposure in Tac combination
In standard patients, no clinical indication for therapeutic drug monitoring
May benefit in dual IS , patient under going CNI- or steroid sparing regimes, high immunologic risk, those with delayed graft function , or those with GI, hepatic or renal function
Drug interactions
-cholecystaramine -reduce MPA absorption
-antibiotics that disrupts GI flore –reduce UGT1 and enters hepatic circulation
-PPI- reduce MPA exposure by 25-35%
-CSA-reduce MPA conc due to reduce enters hepatic circulation
-co administration of Tac do not alter
-MPA with sirolimus – level of MPA higher
-steroids increases MPAG slightly by inducing hepatic glucuronosyl transferase
Cyclosporines
-CSA micemulsions (Neoral) had replaced the original oil based Sandimmune
Absorption and distribution
-bioavailability of microemulsions are better than oil based – less variability in CSA pharmacokinetics
-Cmax of Neoral is higher, and the trough Cmin correlates better with systemic exposure – reflected by AUC
-compared with IV bioavailability of the oral -30% to 45%
-conversion oral to IV form 3:1 dose ratio
-bioavailability of oral form increases with time due to P-gp group inhibitory properties of CSA
-reaches steady state at 4-8 weeks
-CSA -ME reaches max blood conc in 2H
-half life 6-27
-clearance 5-7mls/min/kg
-CYP3A4 primarily enzyme metabolise CSA
-bind predominantly with lipoprotein – toxic effect might exaggerated by low cholesterol and reduced by low cholesterol
ELITE-Symphony
->1600 subjects enrolled
-2 CSA -ME cohorts: normal and reduced dose CSA with MMF and daclizumab induction
-rejection rates after 1 year -25%
Tacrolimus (prograf)
-poor bioavailability
-but rarely require IV
-can be administrated in NG tube or sublingual
-IV dose – 1/3 of total daily dose by oral in 24 H continuous infusion
-sublingual dose usually have of the oral dose
-oral bioavailability -25%
-maximal blood level reached at 1-3 H
-gastric emptying of solids faster in those taking tac – beneficial to those gastric dysmotility disorders
-Diarrhoea increase the absorption of Tac
-Diurnal variation -Cmax morning -greater than those evening dose
Astagraf -Cmax after 2H
Envarsus XR – Cmax 6H
-high affinity for the formed blood elements
-not significant lipoprotein associated
-less unfavourable effect on the chol
-95% is bound to erythrocytes secondary to high conc of FKBP
-cross placenta barrier and enter breast milk
-breast feeding is not recommended
Metabolism and Excretion
-metabolised extensively by CYPP450 3A( 3A4,3A5)
-excreted in bile with minimal renal excretion
Therapeutic Drug Monitoring
-neoral – peak level ( after 2 H post dose)- so C2 may correlate better with drug exposure and clinical events
-tac – trough level is adequate to monitor
CsA
HPLC
– most specific method for measuring unmetabolised
-expensive and labour intensive
Immunoassay
-most common – Abbott ( Chicago IL) fluorescence polarised immunoassay (FPIA)
-has significant cross reactivity with CsA metabolite and over estimates CsA by 45%
Tacrolimus
-Abbott monoclonal antibody based – micro particle enzyme immunoassay (MEIA)- performed an automated instrument
-permits accurate estimation as low as 2ng/ml
-chemiluminescent microparticle immunoassay – detection limit up to 1ng/ml
-electrochemiluminescense immunoassay (ECLIA)- detection limit 0.5ng/ml
Corticosteroids
-Exert effect by blocking T cell derived and APC cytokine and cytokine receptor expression
-hydrophobic and can diffuse intracellularly
-inhibit translocation of factor KB
-inhibit IL-1,2,3,6,TNF-A
-metabolised by hepatic microsomes enzyme systems
Sirolimus
-mTOR inhibitors -key regulator in the process of cell division
-structurally related to tacrolimus
Mechanism of action
-bind to cytoplasm -binding protein
-TOR -regulatory protein in cellular proliferation G1 to S phase
Absorption and distribution
-rapidly absorbed from GIT
-reach high peak at 1-3 H
-oral dosing solutions has lower F than that with tablets
-92% protein bound
-largely metabolised by CYP3A and P glycoprotein
Therapeutic drug monitoring
-chromatography or immunoassay methodologies
-through level 5-15ng/ml depending on use of CsA
Sahar elkharraz
3 years ago
Bioavailability is the extent and the rate of active drug or it’s metabolites enter circulation; it’s depend on on properties of dose form.
Factors Affecting Bioavailability
* Absorption
* Food Effect
* Drug metabolism/ biotransformation.
* Energy dependent efflux transporters.
* Physico-chemical factors
* First pass metabolism
* CYP450 isozymes
Causes of low bioavailability:
– [ ] Oral dose with poor water soluble
– [ ] Insufficient time for absorption
– [ ] Chemical reaction that reduce absorption
– [ ] Age sex stress physical activity
Assessing bioavailability by determine area under a plasma concentration time, plasma drug concentration increase with extend of absorption.
The maximum plasma concentration is when drug elimination rate equal absorption rate.
The drug excreted unchanged in urine; the bioavailability can estimated by measuring the total amount of drug excreted after a single dose by 24 hr collection in urine.
Cyclosporine:
it’s oral dose
pretransplant dose 15mg /kg PO single dose
Post transplant dose 15mg /kg divided dose in first 2 weeks and then 5-10mg /kg divided dose.
Bioavailability of neoral > sandimmune.
Peak plasma time: neoral 1.5-2hr and sandimmune 3.5hr
90% protein binding
Volume distribution 13L/kg
Metabolism by CYP3A4
elimination 8.4 -27hr
clearance 5-7ml/kg
excreted by bile and faces. small amount by urine 6%.
Tacrolimus:
Oral dose
Inhibition T cell activation and proliferation and humoral immunity.
Bioavailability 7-32%
Peak time 0.5 to 6hr
99% protein binding
Volume distribution.05 to 4.7 l/kg
Metabolism in liver by CYP3A4
Excreted by faces
MMF
Inhibition T and B cell proliferation as well as antibody production.
Bioavailability 94% cellcept and 72% myfortic
metabolism by enterohepatic circulation
Peak plasma time 1.5 hr
Protein binding 82-97%
Volume distribution 3.6 L PO
Elimination half life 18hr
excreted metabolites in urine and faces.
Azathioprine:
it’s purine anti metabolites converted to 6 MP
Inhibition synthesis DNA RNA protein and interfere with cellular metabolism.
Well absorbed orally
peak plasma time PO 1-2 hr
protein binding 30%
metabolism by liver
excreted in urine primary as metabolites
References:
By Jennifer Le , Drug Bioavailability, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego
Last full review/revision Oct 2020
Manal Malik
3 years ago
meant by bioavailability of a drugmeans the proportion of drug reach the periphreal blood and change into active form found that can be used by the body.
factors affect bioavaility of adrug
1-absoption
2-food effect
3-drug metabolism biotransformation
4-energy dependent efflux transporters
5-physico-chemical factors
6-first pass metabolism
7- CYP450 isozymes Cyclosporin
bioavaililbility is variable range from 10% to 89% in various populationas result of lipophilliaty
absorption less depend on bile
volume of distribution range from 3 to 5L/kg
maximum concentration about 2 hour
at least 25 metabolites have been identified however theses metabolism are consider less than those of the parent companet
mainly excreated through GIT system. Tacrolimus
The oral bioavailbility was poor and range from 11.2 to 19.1 in previous study
maxima concentration in the blood in 3 hour
volume of distribution is 0.68l/kg
mainly GIT excrection MMF
absorp in small intestine
mean bioavailabiliy of of MPA from oral administeration of MMF estimate at 94.1% relate to i.v.
there is presystemic removal of MPA but enterohepatic circulation compensate for the first pass loss.
oral has 2 peak
first peak of conc one hour
second peak 8 to 12 hours
Azathioprine
6-mercaptopurine undergoes rapid and extensive catabolic oxidation to 6 thiouric acid in the intestinal mucosa and liver by enzyme xanthine oxidase
bioavaibility of 6- mercaptourine range from 5 to 37% in comparison , the intestinal absorption azathiopurine range from 50-72%
peak of conc in the plasma in 1 to 2 hour
volume of distribution is 1.7 l/kg
excerted mainly in the urine References 1.MEHTA MU, VENKATARAMANAN R, BURCKART GJ, et al. Effect of bile on cyclosporine absorption in liver 2-Srinivas TR, Meier-Kriesche HU, Kaplan B. Pharmacokinetic principles of immunosuppressive drugs. Am J Transplant. 2005 Feb;5(2):207-17. doi: 10.1111/j.1600-6143.2005.00748.x. PMID: 15643980.
Mahmud Islam
3 years ago
Bioavailability of a drug refers to the extent to which it drug reaches its destination and target after the initial dose. In terms of our drugs, there may be minor differences between original and generics. combinations also have affect. for example CsA vs TAC will affect the dose of MMF needed. CsA reduces MMF exposure by 40% so we may need less dose on tacrolimus without risk of rejection compared to required dose when combined with CsA (In other words, to reach similar MPA exposure, the dose of MMF/EC-MPS will need to be higher if combined with cyclosporine)
3. What is meant by bioavailability of a drug? What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs? Cyclosporine Tacrolimus MMF Azathioprine
Bioavailability means the extent a substance or drug becomes completely available to its intended target(s). Example: if 10 mg of a drug is given orally & 7 mg of this drug is absorbed unchanged, the bioavailability is 0.7 or 70%). Bioavailability of a drug given by an IV route is by definition 100%. For other routes it is 100% or less. Bioavailability of oral medications depends on: It physiological properties that affect its dissolution and absorption Intestinal pH Surface of absorption Hepatic 1st-pass metabolism Taking with food Clinical implications of bioavailability: When changing a formulation or a route of a drug, the dose needs to be adjusted accordingly. =============================================================
Cyclosporine
– Absorption is mainly in the intestine.
– Absorption is highly variable; peak bioavailability of 30% occurs 1-8 hours after oral dose.
– A 2nd peak seen in certain patients.
– Absorption from the GI is incomplete due to 1st– pass effects.
– Cmax in both the blood & plasma occurs at 3.5 hours post-dose.
– Absorption can be reduced by:
i) Timing & quality of food intake
ii) Interruption of enteric-hepatic circulation (especially after liver transplantation)
iii) Slow gastric emptying
iv) Diarrhea v) Chronic and acute enteritis vi) Intestinal autonomic neuropathy ==================================================================================
Tacrolimus Tacrolimus activity is primarily due to the parent drug. Absorption after oral administration is incomplete & variable. Absolute bioavailablility is 17±10% in kidney transplant patients Cmax occurs at 3.0 hours post-dose. The rate & extent of tacrolimus absorption are greatest under fasting conditions.
Maximum absorption occurs when taken on an empty stomach.
Bile does not influence tacrolimus absorption. Tacrolimus is metabolized primarily by cytochrome P-450 system (CYP3A). ====================================================================
MMF It is a prodrug of mycophenolic acid Reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). Rapidly absorbed in the small intestine. Cmax of its active metabolite, MPA, is at 60 to 90 minutes aftr an oral dose. Bioavailability after oral dose is 94%. Cmax of mycophenolate mofetil was 24.5 (±9.5)μg/mL. ====================================================================
Azathioprine Azathioprine is a prodrug of 6-mercaptopurine. It is metabolized by xanthine oxidase. Xanthine oxidase inhibitors (allopurinol & febuxostat) may inhibit azathioprine metabolism, thus resulting in increased toxicity. Concurrent use of xanthine oxidase inhibitors & azathioprine should be avoided if possible. Otherwise azathioprine dose should be reduced. Oral azathioprine is well absorbed, with a Tmax of 1-2h Peak plasma concentrations are reached 1-2 hours after a dose. Distributed rapidly throughout the body. The plasma half life is 3-5 hours. ======================================================================== References 1.MEHTA MU, VENKATARAMANAN R, BURCKART GJ, et al. Effect of bile on cyclosporine absorption in liver transplant patients. Br J Clin Pharmacol 1988; 25: 579-584. 2.Drug Bank Online 3.MEDICATION GUIDELINES FOR SOLID ORGAN TRANSPLANTS,2021
Dawlat Belal
Admin
3 years ago
Dear all
1.Please look at the table offered by Professor Ala Ali before answering it will save you a lot of time and effort.
2.Pregnancy and TX ,MMF is replaced by AZA and switched back some time after delivery ?
If you know why as I am sure you do
can you explain?
Which is the active metabolite
What is the situation in the Fortal. Lliver enzymes and what happens sometime after birth..
☆ MMF and MPA are teratogenic in animal models, and an increasing body of evidence supports its teratogenicity in humans.
Patients with a desire to become pregnant should discontinue MMF at least 6 weeks before conception.
An increased rate of spontaneous abortion as well as congenital malformations with estimated rate of 25% has been reported, including a distinctive and unique phenotype associated with MMF exposure called the EMFO tetrad (ear, mouth, fingers, ocular/organ malformation).
The FDA has issued a black box warning based on the reports of teratogenicity, and contraception is mandatory for women with childbearing potential.
An early switch from MMF to azathioprine in women planning pregnancy is advised.
Uncertainty remains whether MMF/MPA should be stopped in men, but recent literature has indicated that paternal exposure to MPA is not associated with adverse birth outcomes.
After a switch, a longer observational period confirming stable kidney function or disease activity over time is of interest to reduce the complication rate during pregnancy.
☆ Exposure to azathioprine is reported to increase the risk of preterm and low-birth-weight infants, but no specific pattern or increased risk of malformations has been described. The former might be a direct consequence of the underlying disease rather than an effect of drug exposure.
☆ Both CNIs (cyclosporine A and tacrolimus) are relatively well tolerated during pregnancy: there are consistent reports of low birth weight for gestational age and premature birth but without increased risk of birth defects.
Trough levels may fluctuate during pregnancy due to an increase in enzymatic activity of the CYP3A family, altered volume of drug distribution, and changes in drug-binding components as albumin and hemoglobin levels decrease and the unbound fraction of CNIs increases.
To maintain a stable trough level, a CNI dose increase of approximately 20%-25% may be required during pregnancy. To date, there is no information about pregnancy outcome after voclosporin exposure, but animal data indicate a similar safety profile as observed for other CNIs.
—————–
Reference
Sam Kant, Andreas Kronbichler, Duvuru Geetha, Principles of Immunosuppression in the Management of Kidney Disease: Core Curriculum 2022,
American Journal of Kidney Diseases,2022, ISSN 0272-6386, https://doi.org/10.1053/j.ajkd.2021.12.011
The point of my question is:
The pregnant mother metabolites the AZA in. her liver to 6MP which is the active metabolite.
Then what happens to the feotus if he gets AZA FROM HIS MOTHER which will be toxic.
The feotus does not have the liver enzyme to do that BUT after birth he develops it and that is the mother has to stop AZA after delivery if she tends to breast feed.
The rest of your comments are correct.
What is meant by bioavailability of a drug? Bioavailability of a drug implies the proportion of the drug which reaches the peripheral circulation unchanged, in its active form, on introduction to the body. (1) Bioavailability of an oral drug is calculated by comparing the AUC (area under the curve) or urine recovery of the unmetabolized drug after intravenous and oral administration. (2) The oral bioavailability of a drug can be defined as: Oral Bioavailability = (AUCoral/ AUCintravenous) x 100% Bioavailability of an oral drug depends on: 1) Physicochemical barriers to absorption by the gastrointestinal mucosa 2) Gastrointestinal transit rate 3) First-pass/ pre-systemic metabolism and/or excretion by the gut and/or liver. What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
Cyclosporine: Oral bioavailability: 30-45%, increases with time due to inhibitory effect on P glycoprotein (responsible for efflux of cyclosporine in gut lumen), steady state achieved in 4-8 weeks. Less dependence on bile for absorption with the microemulsion form. Max blood concentration in 2 hours, Volume of distribution: 3-5 L/kg. Food decreases absorption. Primarily eliminated in bile/ faeces, only 6% in urine.
Tacrolimus: Oral bioavailability: 25%. No dependence on bile for absorption. Max blood concentration in 1-3 hours, Volume of distribution: 0.68 L/kg. Food decreases absorption, hence better to give empty stomach. Primarily eliminated in bile/ faeces. Diarrhea may lead to increased absorption from lower GI tract, causing toxic levels.
MMF: It is a prodrug with oral bioavailability: 94%. Max blood concentration in 1 ½ hours, second peak 6-12 hours later due to enterohepatic circulation. Volume of distribution: 0.71 L/kg. Primarily eliminated in urine (93%). Enteric coated MMF absorbed only in small intestine, with peak concentration after 2-3 hours. AUC of mycophenolic acid increases over time. The bioavailability of the drug gets reduced with high fat diet, hence better to take empty stomach to increase absorption. It can be given with food at specific times, if patient has GI effects.
Azathioprine: Oral bioavailability: 47% (27-80%). Max blood concentration in 1-2 hours. Volume of distribution: 0.1 – 1.7 L/kg. Primarily eliminated in urine. It is administered after meals to avoid GI side effects.
References: 1) Broen JCA, van Laar JM. Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology. Nat Rev Rheumatol. 2020 Mar;16(3):167-178. doi: 10.1038/s41584-020-0374-8. Epub 2020 Feb 13. PMID: 32055040. 2) Srinivas TR, Meier-Kriesche HU, Kaplan B. Pharmacokinetic principles of immunosuppressive drugs. Am J Transplant. 2005 Feb;5(2):207-17. doi: 10.1111/j.1600-6143.2005.00748.x. PMID: 15643980.
Bio-availability
It is an important determinant of pharmacokinetic of a drug in which the fraction of total drug administered into the body reaches the systemic circulation in active form. It depends upon first pass metabolism and mode of entrance and blood flow. Bioavailabiloty is 100% in IV route whereas low in other routes
Transplant immunosuppressive drugs have following characters:-
1)Mycophenolate Mofetil :-
* 80% bioavailability
* meal decreases Cmax by 40% but AUC unchanged
* Hence should be taken in empty stomach
* half life -18 hours
2)Mycophenolate Sodium :-
*72% bioavailability
*meal decreases Cmax by 33% but AUC unchanged
* Hence should be taken in empty stomach
* Half life -12 hours
3)Cyclosporin:-
*Oral bioavailability 23-50%
*meal decreases Cmax by 33%
*meal also decreases AUC by 13%
*Ideally should be taken in empty stomach
*Half life 8 hours
*Prolonged in hepatic impairment
4)Tacrolimus:-
*Oral bioavailability 7-23%
*Fatty meal decreases Cmax by 77%
*Fatty meal decreases AUC by 37%
*Though carbohydrate also decreases Cmax and AUC but lesser than Fatty meal
*Half life -12 hour
*Ideally should be taken before meal
Tacrolimus extended release
*Oral bioavailability 12-19%
*Half life of 38 hours
5)Azathioprine:-
*Breakdown to 6-mercaptopurine
*Half life is 3 hours of active metabolite
*Can be taken with or without food
It refers to the exact level of drug that is made available in circulation for intended effects on target receptors after passing through different barriers . It can be affected by intrinsic or extrinsic factors like physical properties of drugs, dose, formulation and concomitant use of other medications ,foods etc. It can be 100 % for intravenous route while significantly lower in oral route. The time taken-Tmax to achieve maximum drug concentration and the actual maximum drug concentration will depend on multiple factors and will be different for each drug.
Cyclosporine
It can be given through IV and oral route and absorption can be affected by multiple factors including metabolism by CYP3A..Any substance which affects cytochrome can affect Cyclosporine bioavailability. Peak bioavailability can be achieved in 1-8 hours. About 50 % can be bound to blood elements like RBC and lymphocytes. It has narrow therapeutic range and close monitoring of drug levels is required. There can be significant drug interactions like phenytoin can reduce serum levels while erythromycin can increase the levels.
Tacrolimus.
It is metabolized by cytochrome CYp3A4/5 and can be given by both oral and intravenous routes. The oral formulation is availabe as 0.5, 01 and 5 mg. It has narrow therapeutic index and bioavailability can be between 5-93%. Oral dose is usually 3-4 times higher than IV dose. In the circulation it bind to proteins and RBCs. Peak level can be achieved in an hour. Metabolism can occur in intestine, liver and kidney. Bioavailability can be affected by multiple factors including diabetes, bowel resection , africo american or non white races.
Azathioprine.
It is an antimetabolite with narrow therapeutic range and bioavailability is around 50-70 percent and metabolized in the liver. After oral administration the absorption is quick and peak plasma levels can be seen in 1-2 hours. It is distributed in body fluids except extracellular fluids . Its use should be avoided along with allopurinol. Leukopenia can result if used with cotrimoxazole or ACE inhibitors. With the arrival of MMF its use has been discontinued mostly.
MMF
It blocks the proliferation of Band T cells by reversibly inhibiting inosine monophosphate dehydrogenase. Its is rapidly absorbed from gut and 90% is bound to plasma proteins. T max can be achieved in 1.5 hours. Absorption can be affected by antacids and cholestyramine. 93 % is eliminated in urine. Its available as 250 mg immediate release and 500 mg Tabs.
References
Handbook of nephrology and hypertension-Simon Steddon
Handbook of kidney transplantation – Gabriel M Danovitch
Drug interactions affecting bioavailability and doses!
Reem Younis
3 years ago
-Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. The bioavailability of a drug is largely determined by the properties of the dosage form, which depend partly on its design and manufacture. Cyclosporine:
-The original formulation of cyclosporine, the oil-based Sandimmune, has largely been replaced by the microemulsion formulation, Neoral.The bioavailability of the microemulsion formulation is better than that of Sandimmune, and there is less variability in cyclosporine pharmacokinetics.
-The improved gastrointestinal (GI) absorption of the microemulsion and lesser dependence on bile for absorption may reduce the necessity for intravenous cyclosporine administration.
-Compared with intravenous infusion, the bioavailability of the orally administered drug is in the range of 30% to 45%. Conversion between the oral and
intravenous forms of the drug perioperatively require a 3:1 dose ratio and is administered twice daily as 4-hour infusions.
– Bioavailability of oral cyclosporine increases with time.
-The amount of cyclosporine required to achieve a given blood level tends to fall with time and typically reaches a steady level within 4 to 8 weeks.
– Food tends to decrease the absorption of cyclosporine, although some foods can lead to increased absorption .
-The microemulsion formula of cyclosporine reaches maximal blood concentrations in approximately 2 hours.
-The volume of distribution is 3 to 5 L/kg, with the majority of the drug found in erythrocytes. It also exhibits very high protein binding in the plasma, especially to lipoproteins.
-The half-life varies from 6 to 27 hours with a clearance of 5 to 7 mL/min/kg.
-The drug is primarily eliminated in the bile with only 6% of the dose excreted in the urine, and with only 0.1% excreted unchanged.
-CYP3A4 is the primary enzyme system that metabolizes cyclosporine.
-In the blood, one-third of absorbed and infused cyclosporine is found in plasma, bound primarily to lipoproteins. Most of the remaining drug is bound to erythrocytes. Whole-blood drug levels are thus typically three-fold higher than plasma levels.
-The binding of cyclosporine to lipoproteins may be important in the transfer of the drug through plasma membranes, and the toxic effects of cyclosporine may be exaggerated by low cholesterol levels and reduced by high cholesterol levels. Tacrolimus :
– it has relatively poor bioavailability, it is rarely necessary to use the intravenous
formulation. If necessary, the drug can be administered through a nasogastric tube or sublingually.
-Intravenous dosing is approximately one-third of the total daily dose required by the oral route and is administered via a 24-hour continuous infusion.
-Sublingual dosing is more variable, but is usually one-half that required by the oral route.
-With the immediate-release dosage forms, it is absorbed primarily from the small intestine, and its oral bioavailability is about 25%, with large interpatient and intrapatient variability, particularly for patients with GI disease.
-Maximal blood concentrations are reached in 1 to 3 hours.
-Diarrhea may lead to increased absorption of tacrolimus from the lower GI tract with resultant toxic levels.
-Immediate-release tacrolimus displays diurnal variation in its absorption profile. Cmax concentrations after morning dosing are typically greater than those found with the evening dose.
-The prolonged-release formulation, Astagraf XL, has a Cmax which occurs after approximately 2 hours, whereas that of Envarsus XR is approximately 6 hours.
– Food has a similar effect on absorption with both the immediate- and prolonged-release formulations as with cyclosporine; patients should be counseled to be consistent in how they take these medications concerning meals.
-Tacrolimus also has a high affinity for formed blood elements, but it differs from cyclosporine in that, although it is highly protein-bound, it is not significantly associated with lipoproteins, and it has a less unfavorable effect on the cholesterol level than does cyclosporine.
-Approximately 95% of the TAC is bound to erythrocytes secondary to the high concentration of FKBP found in these cells. MMF :
– Orally administered MMF is hydrolyzed to MPA and is rapidly absorbed, producing a peak level in approximately 1 hour.
-The bioavailability of MMF is roughly 90%, with 97% of the MPA protein bound to albumin.
– Orally administered MPA exhibits different absorption kinetics owing to
the formulation; the tablets only dissolve under neutral pH conditions, and thus absorption only occurs in the intestine.
-It has a peak concentration after approximately 2 to 3 hours. For African-American patients, a higher dose may be required to produce the immunosuppressive benefit.
-The same doses when used early postoperatively can produce much higher concentrations several months later. Patients should be continuously monitored for adverse side effects and periodically be evaluated for an MPA dose reduction, if clinically appropriate.
– Azathioprine
-It is absorbed from the gut to about 88%. Bioavailability varies greatly between individual patients, between 30 and 90%, because the drug is partly inactivated in the liver. References :
1.Jennifer Le. Drug Bioavailability .MSD MANUALProfessional Version.
2.Danovitch G.M handbook of kidney transplantation sixth edition.
What is meant by bioavailability of a drug?Bioavailability is the fraction of administered drug that reaches the systemic circulation. Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form. For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or seventy percent. Implementation of bioavailability on planning the dose of the following immunosuppressive drugs 1-Cyclosporine non-modified (Sandimmune):its oral bioavailability generally poor and unpredictable:10 to 89% (renal transplant patients) Metabolized by CYP3A4 to reduced activity and inactive metabolites (eg, M1, M9, M4N) cleared fecally via bile so its half life increased with hepatic impairment. –Cyclosporine modified (micro emulsion) (Neoral). 23 to 50% better absorbed than non-modified formulation in renal and liver transplant patients, respectively. Both Should be taken at a consistent time each day in relation to meals. Both affected by high-fat meal. 2-Tacrolimus immediate-release capsule (Prograf) its oral bioavailability 7 to 32%.Metabolized by CYP3A4/5 to active (eg, 13-O-demethyl) and inactive metabolites cleared fecally via bile so its half-life Prolonged in severe hepatic impairment. High-fat meal: ↓C-max by 77% and ↓AUC by 37% Should be taken on an empty stomach. Tacrolimus extended-release capsule (Astagraf XL) its bioavailability 12 to 19% and its half-life is (35 to 41 hrs.) which used mainly with patient with peak dose toxicity as headache or tremors. Tacrolimus extended-release tablet (Envarsus XR) its bioavailability 50% better absorbed than immediate-release capsule. 3-Mycophenolate mofetil (MMF, CellCept)/Mycophenolate sodium, enteric coated (Myfortic) their bioavailability 80.7% and 72% respectively. With tacrolimus decrease dose of MMF but increase with cyclosporine as it interrupt enterohepatic circulation. Should be taken on an empty stomach or at a consistent time each day in relation to meals to improve GI tolerability. Giving total daily dose in three or four equally divided doses may improve GI tolerability. 4-Aazathioprine: Has poor oral bioavailability ( nearly 50 % of oral dose absorbed and so equivalent IV dose is half oral one ). Half-life of parent drug is 12 min but for active metabolite 6-MP is 0.7-3 hours. Slightly prolonged in end-stage renal disease. References: 1-Up to date. 2-Tsipotis E. Gupta N.R, et al (Bioavailability, Efficacy and Safety of Generic Immunosuppressive Drugs for Kidney Transplantation: A Systematic Review and Meta-Analysis),American Journal of Nephrology,2016, Vol.44, No. 3.
Good but you all missed the purpose of the question which is the effect on dosing.
Drug interactions?!
Murad Hemadneh
3 years ago
Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. Bioavailability of a drug is largely determined by the properties of the dosage form, which depend partly on its design and manufacture.
For intravenous route bioavailability is 100%, while in other routes of administration such as oral route it could be lower due to first pass effect.
Drug bioavailability after oral administration is affected by a number of different factors, including physicochemical properties of the drug, physiological aspects, the type of dosage form, food intake, biorhythms, and intra- and interindividual variability of the human population. Accordingly immunosuppressant agent should be monitored by assessing their blood level.
Cyclosporine:
Mechanism of Action: Calcineurin inhibitor, suppresses cellular and humoral immunity (mainly T cells).
Forms: Modified (Neoral) and Non-Modified (Sandimmune).
Bioavailability: Modified (Neoral) has better absorption up to 30% and less dependant on food, bile acids and GI motility. Incomplete absorption of cyclosporine mostly related to the first pass effect. Absorption of cyclosporine is highly variable. Peak plasma time: Neoral 1.5-2 hr; Sandimmune 3.5 hr.
Distribution: Protein Bound: 90%, Volume of distribution (Vd): 13 L/kg.
Dose: 15 mg/kg/day PO divided BID Reduce 5% per week until: 5-10 mg/kg/day PO divided BID. if IV then third oral dose (5mg/kg/day).
Therapeutic window: Narrow, 500-600 ng/ml in the first week of post-transplantation, 600-800 ng/ml in the second week to sixth month of post-transplantation, 400-600 ng/ml in the seventh to twelfth month of post-transplantation and 350-400 ng/ml 1 year after post-transplantation.
Should taken consistently with relation to meals.
Tacrolimus:
Mechanism of Action: Calcineurin inhibitor; inhibits T-cell activation and proliferation, humoral immunity Macrolide antibiotic; potent immunosuppressant.
Bioavailability: 7-55% (children); 7-32% (adults). Peak plasma time: 0.5-6 hr. Has incomplete and variable GI absorption. Absorption is decreased by food 27%.
Metabolism: Metabolized in liver by CYP3A4, level may differ between patients taking the same dose depending on the activity of cytochrome B450 leading to significant inter-patient variation.
Dose: PO (with azathioprine): 0.2 mg/kg/day divided q12hr, PO (with MMF/IL-2 receptor antagonist): 0.1 mg/kg/day divided q12hr, IV: 0.03-0.05 mg/kg/day IV by continuous infusion.
Therapeutic window: Narrow, 5 to 15µg/L may be more appropriate.
Recommended to be taken on empty stomach either 1 h before or 2 hours after meals.
MMF:
Mechanism of Action: Acts as non-competitive, selective, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), Inhibits T- and B-cell proliferation, as well as antibody production. Is a Pro-Drug and it’s active compound mycophenolic acid(MPA).
Forms:CELLCEPT (mycophenolate mofetil MMF) and MYOFORTIC(mycophenolic acid MPA).
Dose: Mycophenolate mofetil (MMF): 1 g PO/IV q12hr, Mycophenolic acid (MPA): 720 mg PO q12hr. Cyclosporinedecrease level of MMF, so the recommended dose of MMF when used with cyclosporine is 2 gm, while when used with tacrolimus the dose can be reduced to 1 gm daily.
Can be administered with or without food but in in relation to meals to improve GI tolerability.
Azathioprine:
Mechanism of Action: Purine antimetabolite, converted to 6-MP (pro-drug); may inhibit synthesis of DNA, RNA, and proteins; interferes with cellular metabolism; may inhibit mitosis.
Metabolism: Metabolized in liver, Metabolites: 6-MP and 6-thiouric acid.
Elimination: Half-life of parent drug is 12 min but for active metabolite 6-MP is 0.7-3 hours. Slightly prolonged in end-stage renal disease. It’s partially dialyzable and excreted via urine (primarily as metabolites).
Dose: 3-5 mg/kg/day IV/PO initially on day of transplant then maintenance dose of 1-3 mg/kg/day IV/PO.
Allopurinol should be used with great caution with azathioprine because AZA is metabolized by xanthine oxidase and potentiate myelo-suppression.
Can be administered with or without food.
References:
Xu F, Chen ZL, Jin WJ, Xie QD, Shi XH. Ideal therapeutic range of cyclosporine in whole blood in kidney-transplanted patients. Int J Clin Pharmacol Res. 1993;13(4):221-4. PMID: 8150548.
Burckart GJ, Starzl TE, Venkataramanan R, et al. Excretion of cyclosporine and its metabolites in human bile. Transplant Proc. 1986;18(6 Suppl 5):46-49.
Ball S. Bioequivalence of twice-daily oral tacrolimus in transplant recipients: More evidence for consensus?. PLoS Med. 2017;14(11):e1002429. Published 2017 Nov 14. doi:10.1371/journal.pmed.1002429
Antignac M, Barrou B, Farinotti R, Lechat P, Urien S. Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients. Br J Clin Pharmacol. 2007;64(6):750-757. doi:10.1111/j.1365-2125.2007.02895.x
Bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered.
The route of administration and the dose of a drug have a significant impact on both the rate and extent of bioavailability. The dose of a drug is indirectly proportional to its bioavailability.
Cyclosporine
In plasma, it is 90% protein bound, mostly to lipoproteins.
In blood, cyclosporine is extensively distributed in erythrocytes. There is significant interindividual variability in intestinal absorption, furtherly influenced by food , diabetes, gastric motility problems, and diarrhea .
It’s variability in intestinal absorption has been solved by the creation of the microemulsion formulations.
CsA is metabolised by the cytochrome P450 system, primarily CYP3A4, and CYP3A5 . Coadministration of medications known to inhibit the cytochrome P-450 system increase cyclosporine levels ,while inducers of the P-450 system decrease it’s levels .
CsA nephrotoxicity is dose dependent and reversible upon dose reductions or discontinuation of the drug.
It was noticed that using a dose of 25 mg/kg had a significant unexpected nephrotoxicity.
Follow-up studies using a lower dose (17 mg/kg) showed improved outcomes with this strategy with a one-year predicted graft survival rate of 86%.
Other studies have also demonstrated improved GFR and blood pressure measurements using a target of fifty percent of the standard area-under-the-curve (AUC) dose
Meanwhile the desire to reduce CsA exposure without risking under immunosuppression led to protocols including other immunosuppressive agents as using of antilymphocytic antibodies in the early posttransplant period in an attempt to avoid early CsA exposure until such time that allograft function was fully recovered.(1)
Tacrolimus
It has narrow therapeutic index (between 5 and 15 ng ml) and wide intra- and interpatient variability.
The oral bioavailability of tacrolimus is poor could be due to gut metabolism or to poor oral absorption of the drug, because of this it is administered intravenously during the immediate postoperative period.
There is a significant correlation between increased Tac .trough concentration and decreased risk of acute rejection, but there is a poor correlation between it’s dose and trough concentrations.
when prednisone dosage was >25 mg, Tac clearance was increased, it could be due to corticosteroid induction of CYP3A.(2)
The immediate-release formulation of tacrolimus was administred twice daily (IR-Tac and generics, Prograf) and in order to improve treatment adherence, tacrolimus was formulated as a prolonged-release once-daily formulation (PR-Tac, Advagraf) which improved adherence, having also non-inferior efficacy and similar tolerability compared to IR-Tac.
A novel once-daily formulation of tacrolimus was developed based on the MeltDose drug delivery technology (LCPT, Envarsus) enhancing the bioavailability of low water solubility drugs by decreasing its particle size, thereby controlling its release and allowing a more distal distribution of the drug within the gut,with a 30% reduction of total daily dose (TDD) and a lower peak and less peak-to-trough fluctuation.
Studies reported the higher bioavailability of LCPT versus PR-Tac and a lower incidence of BK infections .(3)
MMF
MMF is an ester prodrug of mycophenolic acid (MPA) and MPA has a narrow therapeutic window and large inter-individual variability, therforetherapeutic drug monitoring (TDM) of the area under the concentration–time curve for the 12-h of exposure (AUC0-12 h) of MPA (MPA-AUC0-12 h) is essential to improve clinical outcomes.
The two formulations of MMF ;dispersible tablet and capsule were bioequivalent
When giving 750 mg twice daily, most patients can reach the target exposure in 1st week after renal transplantation.
An appropriate AUC0-12 h after drug administration, between 30–60 μg⋅h/mL, was associated with significant decrease in acute graft rejection
TDM of MPA is significant in performing personalized prescription for the prognosis of recipients.
The C0 level was not a reliable parameter to assess the MPA exposure .
The 4-point method (C8, C2, C4, and C1) was the best Limited sampling strategy (LSS), it was recommended for predicting MPA-AUC0-12 h in early renal transplant recipients
The concomitant use of cyclosporine lowered MMF level more than concomitant Tac administration.(4)
Azathioprine
It is well absorbed following oral administration. The absolute oral bioavailability is estimated to be between 41% and 47%. Protein binding of azathioprine is approximately 30% and it is partially dialyzable.Metabolites of azathioprine are primarily excreted via the kidney, with very small amounts of the parent compound excreted intact. The t1/2 of azathioprine is approximately 3 hours.(5)
Studies demonstrated that, in tacrolimus-based immunosuppression, azathioprine may be as good as MMF as maintenance immunosuppressive drug in living donor kidney transplantation particularly it is a more cost-effective immunosuppression.(6)
Reference
1-Tedesco D.etal .Cyclosporine A Review Journal of Transplantation2012 , Article ID 230386, 7 pages
2- M. Antignac et al. Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients. Br J Clin Pharmacol 64:6 750–757
3-FernandezRiveraetal.Bioavailability of once daily tacrolimus formulations used in clinical practice in the management of DeNovo kidney transplant recipients :the better study. Clinical Transplantation.2022;36:e14550.
4- Zhang J. et al. Pharmacokinetics of Mycophenolate Mofetil and Development of Limited Sampling Strategy in Early Kidney Transplant Recipients.Frontiers in Pharmacology 2018;9;908.
5-Chaballa M etal .Transplant Medicine. Pharmacology and Therapeutics .Principles to Practice 2009, 1269-1294.
6- Bansal S .B .etal.Comparison of azathioprine with mycophenolate mofetil in a living donor kidney transplant programme.Indian J Nephrol. 2011 Oct-Dec; 21(4): 258–263.
Well done though you give the impression that TAC is routinely given Iv early post transplant..?
Ahmed Abd El Razek
3 years ago
bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered.
It is affected by many factors the most important is the mode of administration , first pass effect, other medications, protein binding , ingested food, dose , concentration and the volume of distribution.
Cyclosporine is a lipophilic polypeptide. The enteric oral absorption of cyclosporine is a process dependent on bile salt secretion. Furthermore, many physiological and pathological conditions, such as timing and quality of food intake, interruption of enteric-hepatic circulation , slow gastric emptying, diarrhea, chronic and acute enteritis, intestinal autonomic neuropathy and alterations of gastroenteric functionality among others, can significantly reduce cyclosporine absorption. These conditions can cause a considerable inter- and intra-patients variability in gastrointestinal absorption. Also cyclosporine bioavailability after oral administration varies between 20 and 60% of the given dose and increases with time after kidney transplantation
Regarding tacrolimus
The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1% in adult kidney recipients.
The low bioavailability of tacrolimus could be due to gut metabolism or to poor oral absorption of the drug. Incomplete absorption of tacrolimus is largely responsible for the low bioavailability of the drug .
Some factors, such as changes in gastrointestinal motility after surgery, could explain the low clearance immediately after surgery and recovery after a few days. After a long duration of surgery, as in transplantation, some disorders have been observed and the time to obtain the maximal value for clearance could correspond to the recovery of metabolic function
A significant relation is found between tacrolimus clearance and oral corticosteroid dosage during months 2–12 post transplantation in kidney transplant recipients, indicating that corticosteroids increased the metabolism of tacrolimus.This could have resulted from corticosteroid induction of CYP3A.
Tacrolimus, however, is poorly bioavailable in patients awaiting renal transplantation (mean bioavailability of 14%, range 6–36%)
MMF
a prodrug of mycophenolic acid (MPA), after oral and intravenous administration. The plasma MPA profile of oral MMF showed a sharp peak at approximately 1 hour and a secondary peak at 8 to 12 hours. Mean apparent plasma t1/2 of MPA was similar for both routes (approximately 17 hours).
The mean bioavailability of MPA from oral administration of MMF estimated as 94.1% relative to the intravenous route.
Azathioprine is well absorbed following oral administration. The absolute oral bioavailability is estimated to be between 41% and 47%. Protein binding of azathioprine is approximately 30% and it is partially dialyzable. Azathioprine undergoes metabolism to 6-MP in the liver . 6-MP undergoes further metabolism via oxidation and methylation in the liver and in erythrocytes. Metabolites of azathioprine are primarily excreted via the kidney. The t1/2 of azathioprine is approximately 3 hours.
Ala Ali
Admin
3 years ago
Check this and comment
Ala Ali
Admin
3 years ago
Comment on this graph according to the above-mentioned Medications.
MMF has 2 peaks of concentration in the blood : the 1st peak after 1.5 hours, the 2nd peak after 6-12 hours because of the enterohepatic circulation, therefore the bioavailability of MMF is higher than azathioprine and tacrolimus.
_ simply, drug bioavailability means the proportion or the drug that reaches the systemic circulation to be available at the target site of action, which is affected by many factors in case of Oral drugs as immunosupressives used in the field of transplantation.
_ the drug bioavailability can be detected be comparing the plasma concentration of the drug after oral and IV route of administration.
_ factors affecting it are the drug dose, formulation, solubility , absorption, metabolism and 1st pass metabolism in liver or intestine which have marked intra and inter individual variability.
_ as regard CNI:
a. For both ciclosporin and tacrolimus
b. It’s metabolized by cytochrome P450 ( it’s subtypes CYT P 3A4 and 3A 5 which are affected by many factors:
_ drugs as enzyme inducers like phenytoin and rifampin which can increase drug elimination and predispose to rejection, or enzyme inhibitors as antifungal )ketoconazole or antibiotics like erythromycin) which increase trough level and predispose to CNI induced toxicity as nephrotoxicity with ciclosporin and neurotoxicity with tacrolimus. _ the concept of increased Tacrolimus trough level by ketoconazole has been utilized to decrease required dose and financial burden.
I think also phenobarb can be used to manage drug intoxication.
_ pharmacogenetics also play a role , as individual variation in Cyt 3A4 and multidrug resistant gene (MDR1) which encodes for glycoprotein P-gp which is intestinal and hepatic efflux protein for such drugs makes some people slow metabolizers of the drug and liable to toxicity and others rapid metabolizers and liable to rejection.
_ in addition, lipophilic nature of ciclosporin makes it high volume of distribution and render it’s efficacy in some patients with excess fat tissue and hyperlipidemia ( only small proportion of the drug available at site of action).
_ other drug drug interaction as statin which are also metabolized by CYt p enzyme, so concomitant use may increase competition on enzyme binding site and enhance toxicity of either of them ( rhabdomyolysis from increased statin or nephrotoxicity from CNI).
As regard tacrolimus:
_ the same as ciclosporin , but less oral bioavailability in addition has rapid emptying time so increase risk of toxicity in patients who have diarrhea
_ As regard MMF: either prodrug mycophenolate mofetil or active mycophenolic acid (MPA, myfortic) , enteric coated
With less GIT side effects with mycophenolate mofetil.
_ MMF is extremely affected and poorly absorbed by fatty meals , so should be taken on empty stomach
_ as regard azathioprine ( anti proliferative): its use has declined and replaced by the more potent MMF.
_ poor oral bioavailability ( nearly only 50 % of oral dose absorbed and so equivalent IV dose is half oral one ).
– serious BM depression occurs when used together with allopurinol so better reduction of dose to half or avoided .
_ use of cholestyramine chelates of these drugs especially MMF , so better taken away from time of medications
Use of Lipid apharesis in case of multidrug resistant nephrotic syndrome to control dyslipidemia and enhance response to steroid and CNI , explains how pharmacokinetics greatly influence response to drugs and emphasize importance of control of hyperlipidemia to achieve adequate response to CNI
Implementation of drug bioavailability on planning the dose:
Cyclosporine: Oral bioavailability: 30-45%, increases with time due to inhibitory effect on P gp (efflux of cyclosporine in gut lumen), steady state achieved in 4-8 weeks. Less dependence on bile for absorption with the microemulsion form. Max blood concentration in 2 hours, Volume of distribution: 3-5 L/kg. Food decreases absorption. Primarily eliminated in bile/ faeces, only 6% in urine. Either taken with or without food, and since food may decrease the absorption of cyclosporine it should taken consistently with relation to meals, to adjust trough level accordingly.
Tacrolimus: Oral bioavailability: 25%. Max blood concentration in 1-3 hours, Volume of distribution: 0.68 L/kg. Food decreases absorption, hence better to give empty stomach. Primarily eliminated in bile/ faeces. Diarrhea increases its absorption from lower GI tract, causing toxic levels.
MMF:
o It is a prodrug with oral bioavailability: 94%. Max blood concentration in 1 ½ hours, second peak 6-12 hours later due to enterohepatic circulation. Volume of distribution: 0.71 L/kg. Primarily eliminated in urine (93%).
o Enteric coated MMF absorbed only in small intestine, with peak concentration after 2-3 hours. AUC of mycophenolic acid increases over time.
o The bioavailability of the drug gets reduced with fatty diet, hence better to take empty stomach to increase absorption.
Azathioprine: Oral bioavailability: 47% (27-80%). Max blood concentration in 1-2 hours. Volume of distribution: 0.1 – 1.7 L/kg. Primarily eliminated in urine. It is given after meals to avoid GI side effects.
Drug interactions
Cyt P450 inhibitors as CCB, erythromycin or ketoconazole increase trough level of CNI:so proper action either avoidance of combination or decease dose of CNI used to avoid toxicity. Ketoconazole was used to decrease required CNI dose and cost.
Cyt P450 inducers as phenytoin, rifamicin and phenobarbiturates decrease level of CNI; so proper action to use higher CNI doses to avoid rejection.
Statin may increase the level of tacrolimus
Cyclosporine and not tacrolimus decrease level of MMF, so the recommended dose of MMF when used with cyclosporine is 2 gm, while when used with tacrolimus the dose can be reduced t 1 gm daily
Corticosteroids may decrease the level of MPA so some recommends reduction of the dose of MMF when starting steroid free protocols.
PPIdecrease absorption of MMF but not EC-MPS.
Aluminum or magnesium hydroxide antacids should not be taken at the same time with MMF as they reduce the its absorption
Sevelamer and cholestyramine should not be given within 2 hours after administration of MMF
saja Mohammed
3 years ago
What is meant by bioavailability of a drug? What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
bioavailability is stated to as the level and degree to which the active drug element or active fraction of the product is absorbed and becomes available at the site of drug action.
Measured by Using the area under the blood or plasma concentrate time cure (AUC), or maximum concentration max (con.)
Bioequivalent mean if we have two formulation of the same drug or two drug products like generic product but is assume that they will provide same therapeutic effect and can be used interchangeably means they contain same active ingredient but not necessarily in the same dosage form or same salt or ester in other word they are pharmaceutical equivalents.
Generic drugs mean they are identical to the brand name, FDA approved their use o in order to make it available with less cost, safe with similar efficacy to original brands after validation by bioequivalence clinical trials taken in consideration the drug absorption profiles, therapeutic efficacy, and safety.
Cyclosporine:
Selective inhibition of calcineurin by impair the IL2 transcription inhibition T cells its lipophilic molecules with large volume of distribution, dose not cross the BBB, available as modified and non-modified formula, oral formulation is partially absorbed with large inter-an intra individual variation, oral bioavailability is limited due to poor absorption, partial metabolism by the intestinal enzymes, first-pass, hepatic metabolism via cytochrome 450,cyp3A , P-gp efflux which can be affected by enzymes inducers or inhibitors drugs with the risk of under suppression or CNI toxicity respectively , excreted into the bile and liver dysfunction can prolongs the Half-life Tacrolimus:
Similar to cyclosporine, tacrolimus ( prograf ),oral and IV
Immediate release capsules can be used every 12 hours, low oral bioavailability around 25%, absorption by small intestine with large inter and intra patient variability, maximum blood concentration reached in 1-3 hours with rapid gastric emptying compared to cyclosporine, that’s why the risk of tacrolimus toxicity is more in patient with diarrhea and motility disorders due to increased absorption of the tacrolimus from lower gut and increase drug level
Immediate release formula has diurnal variation in its absorption profile, Cmax aftr morning dose more than evening dose.
While XR formulation, has Cmax after two hours, and envarsus xr after 6 hours
oral suspension formula available.
Many generic brands with conversion ratio of 15% from the original brand, close monitoring with trough level
Long-acting formula available like astagrafXL , envarsus XR , FDA a approved ,used once /day
GI absorption is independent of bile salt, poor bioavailability, IV formula also available with dose conversion one third of total oral dose by 24 h infusion, can also give through NGT and sublingual variable dosing but usually use one – half the total oral dose
MMF:
Active drug related to mycophenolic acid and mofetil moiety serves as important part that enhance the oral bioavailability, MPA is very selective antimetabolite, with selective effect on lymphocytes and blocks the proliferation of T and B cells, inhibits Abs production and inhibits the generation of cytotoxic T cells also downregulation of the adhesion molecules on lymphocytes so its effective in treatment of ongoing rejection and prevent the progression
Both MMF ( cellcept) is the morpholinoethyle ester of MPA, available in the immediate release 250mg capsules and 500mg tablets , also there is suspension formula
The enteric coated MPA ( myofortic ), delayed release formulation of MPA both available as generic form as well
MMF rapidly absorbed after oral administration, produce peak level after 1 hour with 90% bioavailability high protein bound 97%, absorption affected by the PH and need neutral PH. Peak concentration reached after 2-3 hours, in black African American patients need higher dosesAUC of MPA increases overtime and need close monitoring for the side effects and careful dose adjustment.
Safety concern including GI side effects most common diarrhea around 1/3 of cases, dose related
CMV infection, Bone marrow suppression Therapeutic drug monitoring not done in routine practice but in case of side effects sending the AUC for MPA may require for dose adjustment
Only Cyclosporine lowers MPA concentration by decreasing the enterohepatic recycling via OATPIBI inhibition and MPA trough level increase when cyclosporine discontinued
Some drugs interfere with the intestinal absorption of MMF and should avoid given such drug at same time with MMF like antacids , oral iron supplements , sevelamer
Azathioprine:
Purine analogue its antimetabolite that act on inhibition of purine synthesize and interfere with synthesis and metabolism of ribonucleic acid RNA so it inhibits gene replication, cheap immunosuppression has been in use for more than 50s earlier with steroid then with cyclosporine combination, in the era of MMF nowadays its use individualized for specific conditions, it’s a potent myelosuppressive therapy that suppress the promyelocytes in the bone marrow and further inhibit the differentiation of the myelocytes to macrophage in primary immune response.
half of the oral dose will be absorbed and IV dose equivalent to the half oral dose
main side effects, hematological myelosuppression, need regular monitoring with FBC, wbc count and platelet count
also, can cause hepatitis and pancreatitis in less extent, combination with allopurinol should be avoided or used with caution and reduction of the dose by 25-50% with close monitoring with FBC.
References:
1-Chow SC. Bioavailability and Bioequivalence in Drug Development. Wiley Interdiscip Rev Comput Stat. 2014;6(4):304-312.
2-Kidney transplant hand book 6th edition.
1- Up to date medicine .
☆ Bioavailability is the extent a substance or drug becomes completely available to its intended biological destination. It’s a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
° Bioavailability is an integral part of the pharmacokinetics paradigm. Pharmacokinetics is the study of drug movement through the body and is often represented by the acronym ABCD which stands for administration, bioavailability, clearance, and distribution.
° The bioavailability of a drug may be affected by intrinsic or extrinsic variables.
Intrinsically, a drug’s bioavailability can be affected by the drug’s required metabolic steps to activation, the specificity of its target receptors, the patient’s unique physiology (including phenotypic polymorphisms), route of administration of the drug, and site of drug absorption.
Extrinsic variables affecting drug bioavailability include interactions with concurrent food or substance metabolic processes and drug interactions with medications.
° The bioavailability (F) of a drug delivered via other routes of administration can be determined by the mass of the drug delivered to the plasma divided by the total mass of the drug administered (Equation 1):
Equation 1: F = mass of the drug delivered to the plasma ÷ total mass of the drug administered
Bioavailability can be derived from an area under the curve (AUC) graph (Equation 2).
Equation 2: F = AUC for X route of administration ÷ AUC for IV administration
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☆ The oral bioavailability of MMF is 94%, with half-life of approximately 17.9 ± 6.5 hours.
The metabolism of MMF is hepatic, where it is hydrolyzed to MPA and a component of enterohepatic circulation.
Dose reduction should be considered in severely decreased kidney function given the MMF AUC is increased 75% with estimated glomerular filtration rate (eGFR) <25-30 mL/min/1.73 m2, with no adjustment recommended in the setting of severe hepatic parenchymal disease.
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☆ The bioavailability of azathioprine is 16%-50%, with predominant hepatic metabolism. The elimination half-life is about 2 hours, with excretion primarily in the urine.
Dose reduction is usually recommended in the setting of oliguria/acute tubular injury. Genetic polymorphisms of certain enzymes play an important role in the metabolism of azathioprine, namely thiopurine S-methyltransferase (TPMT) and nucleoside triphosphate diphosphatase (NUD15).
Deficiency of TPMT can cause accumulation of 6-thioguanine nucleotides and 6-methylmercaptopurine, leading to hematological toxicity and hepatotoxicity.
Xanthine oxidase inhibitors (allopurinol and febuxostat) should be avoided during azathioprine use, given the risk of accumulation of 6-mercaptopurine by slowing elimination, with consequent serious toxicity.
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☆ The bioavailability of tacrolimus is variable (17% ± 10%), with a half-life of 23-46 hours; the bioavailability of cyclosporine is 30%-68%, with half-life of 5-18 hours.
The suboptimal bioavailability of both drugs is attributed to poor intestinal absorption, partial enzymatic metabolism in gastrointestinal mucosa, and first-pass hepatic metabolism.
Both CNIs are metabolized by the CYP3A system and are excreted via the biliary route (liver dysfunction prolongs the half-life of both drugs).
It is recommended that tacrolimus immediate release and cyclosporine be monitored with 12-hour trough levels.
Dose changes are usually reflected in 2-3 days for both CNIs. For tacrolimus, dose adjustments of 0.5-1.0 mg per dose should occur depending on trough levels; the range for change for cyclosporine is 25-50 mg.
It is imperative to verify whether the trough levels guiding these changes are accurate in relation to timing of administration.
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Reference
(1) Sam Kant, Andreas Kronbichler, Duvuru Geetha, Principles of Immunosuppression in the Management of Kidney Disease: Core Curriculum 2022,
American Journal of Kidney Diseases,2022, ISSN 0272-6386, https://doi.org/10.1053/j.ajkd.2021.12.011
(2) Price G, Patel DA. Drug Bioavailability. [Updated 2021 Sep 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.
(3) Tsipotis E, Gupta N, R, Raman G, Zintzaras E, Jaber B, L: Bioavailability, Efficacy and Safety of Generic Immunosuppressive Drugs for Kidney Transplantation: A Systematic Review and Meta-Analysis. Am J Nephrol 2016;44:206-218. doi: 10.1159/000449020
Bioavailability is an integral part of the pharmacokinetics paradigm. Bioavailability refers to the extent a substance or drug becomes completely available to its intended biological destination(s). More accurately, bioavailability is a measure of the rate and fraction of the initial dose of a drug that successfully reaches either; the site of action or the bodily fluid domain from which the drug’s intended targets have unimpeded access.
What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
Cyclosporine
The original formulation of cyclosporine, the oil-based Sandimmune, has largely been replaced by the microemulsion formulation, Neoral. Both formulations are available in two forms: a 100-mg/mL solution that is drawn up by the patient into a graduated syringe and dispensed into orange juice or milk, and 25-mg and 100- mg soft-gelatin capsules.
The bioavailability (F) of the microemulsion formulation is better than that of Sandimmune, and there is less variability in cyclosporine pharmacokinetics. the bioavailability of the orally administered drug is in the range of 30% to 45%.
In the blood, one-third of absorbed and infused cyclosporine is found in plasma, bound primarily to lipoproteins.
Tacrolimus
Tacrolimus (Prograf ) is available in an intravenous formulation, and as 5-mg, 1-mg, and 0.5-mg immediate-release capsules.
A suspension formula can be compounded, but is not commercially available. GI absorption is independent of bile salts. Despite its relatively poor bioavailability, it is rarely necessary to use the intravenous formulation. If necessary, the drug can be administered through a nasogastric tube or sublingually. Intravenous dosing is approximately one-third of the total daily dose required by the oral route and is administered via a 24-hour continuous infusion.
Both cyclosporine and tacrolimus are metabolized extensively by the cytochrome P450 (CYP) 3A enzymes, specifically 3A4 and 3A5. This primarily occurs in the small intestine, liver, and to a certain extent in the kidney. Both agents and their metabolites are also substrates for P-glycoprotein (P-gp) efflux pumps.
MMF
CellCept is the morpholinoethyl ester of MPA and is available for clinical use in immediate release 250-mg capsules and 500-mg tablets. A suspension formulation is also commercially available. The standard dose is 1 g twice daily. An intravenous preparation is available but is usually not required in kidney transplant recipients. Myfortic (ecMPA) is a delayed-release formulation of MPA as a sodium salt and is available in 180-mg and 360-mg tablets: the standard dose when used is 720 mg twice daily.
The pharmacokinetics of MPA is complex. Orally administered MMF is hydrolyzed to MPA presystemically and is rapidly absorbed, producing a peak level in approximately 1 hour. The bioavailability of MMF is roughly 90%, with 97% of the MPA protein bound to albumin.
MPA is glucuronidated via glucuronyl transferase enzymes in the liver to a pharmacologically inactive form (MPAG). Enterohepatic cycling of MPAG can occur via OATP transportation of MPAG from the liver into the bile.
Neither MMF nor MPA is dialyzed.
Azathioprine
Azathioprine (Imuran) is an antimetabolite, an imidazole derivative of 6-mercaptopurine.
When cyclosporine was introduced, the role of azathioprine was largely relegated to that of an adjunctive agent, and with the introduction of MMF, its use has been discontinued in many programs.
The absorption of orally administered AZA is rapid. Peak plasma concentrations of 6MP, an intermediate metabolite of AZA, has been observed within 1-2 hour.
studies demonstrated that AZA is rapidly converted into 6MP. doses are still based on body weight. Typically, patients undergoing renal transplantation do not receive more than 3 mg/kg orally except in the first few days after transplantation.
Cyclosporine is found in plasma and RBCs otherwise well done
Ban Mezher
3 years ago
Bioavailability: is a fraction of drug that reach systemic circulation or it is a degree or rate of substance ( e.g. dug) that absorbed into circulation or made available at site of physiological activity. There are several factors affect bioavailability:
first-pass hepatic metabolism
solubility of drug
chemical instability of drug
nature of drug formulation.
Cyclosporine:
Can be given orally or through IV route. It has variable oral absorption & inter- & intra-individual variability ( e.g. some patient receive same dose may had acute rejection while other develop toxicity with same dose), & this may be due to its metabolism by CYP3A4 in GIT ( had many interaction with substances can induce or suppress this cytochrome).
50% of the drug bound to blood fraction( 1/2 bind to RBC & <1/10 bind to lymphocytes). So it has narrow therapeutic range & many substances interaction & need close monitoring of drug level.
Tacrolimus:
Can be given orally or IV infusion, but oral absorption incomplete & variable, so need dose tailoring. It metabolized through CYp3A4/5 ( similar to cyclosporine, & drug that can affect metabolism of this cytochrome can affect drug level of tacrolimus). Bioavailability range from 5-93%( narrow therapeutic range), in general oral dose should be 3-4 times higher than IV dose.It highly bound to serum protein & RBC (99%). It absorbed rapidly with peak concentration 0.5-1 hour.
Bioavailability can be reduced in:
patients waiting renal transplant
smaal bowl recipients with open stoma
African-American & non Caucasian
Diabetic patients.
Azathioprine:
Metabolized in liver to 6-mercaptopurine then to thioinosinic acid. Bioavailability 50-72%, & 30% of drug is bound to albumin, once enter the circulation distributed widely throughout the body except CSF. Had long duration of action with narrow therapeutic range.
Using with ACEI or cotrimoxazole can enhance leukopenia, also it should be avoid AZA use with allopurinol ( if used together the dose of AZA should be reduced by 60-75%.
MMF:
potent reversible inhibitor of inosine monophosphate dehydrogenase, so it rapidly block proliferation of both T & B cells. Highly bound to plasma protein( >90%). Rapidly & completely absorbed after oral administration. Several drugs can reduce its absorption e.g. antacid containing Mg & AL, & cholestyramine.
Fine you missed some doses.
How canTAC bioavailability be affected by long waiting time?
Weam Elnazer
3 years ago
What exactly is meant by the term “bioavailability of a drug”?
bioavailability is defined as the proportion of the active form that enters the systemic circulation unmodified.
Tacrolimus:
Cytochrome P450 3A4 (CYP3A4) is the major isoenzyme responsible for the metabolism of tacrolimus and other anti-inflammatory drugs.
Extrahepatic metabolism by CYP3A4 in the gastrointestinal epithelium is responsible for approximately half of the absorbed dosage being eliminated before it reaches the liver.
CYP3A4 in the liver is responsible for an extra 10% of total elimination, resulting from first-pass metabolism.
tacrolimus immediate-release capsule (Prograf)bioavailability varies from 7 to 32 per cent when taken orally.
Cyclosporin:
Cyclosporin’s bioavailability varies from person to person. The percentages ranged from 10 per cent to 89 per cent. The peak bioavailability occurs 1-8 hours after the intake of the medication.
There are clinically significant pharmacological interactions between CsA and a variety of different medicines. Some drugs, such as phenytoin, can lower trough blood CsA concentration to subtherapeutic levels, whilst other drugs, such as erythromycin, can elevate CsA concentrations to potentially dangerous levels.
MMF:
There are two forms of mycophenolic acid (MPA) on the market: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). MMF is a prodrug that was created in order to increase the bioavailability of MPA in patients. By delaying the release of MPA into the small intestine rather than the stomach, EC-MPS has the potential to lower the occurrence of unfavourable gastrointestinal (GI) symptoms, primarily diarrhoea.
The bioavailability of both formulations is roughly 90%, but when taken with a high-fat meal, the bioavailability is dramatically lowered to approximately 80%. Because of this, both formulations should be consumed on an empty stomach in order to maximize absorption.
Azathioprine: is a medication that is well absorbed after being taken orally. The peak in serum radioactivity occurs 1 to 2 hours following oral administration of the radioisotope. The fact that only a part of the radioactivity is present as azathioprine is a result of extensive metabolism.
REFERENCES
-Up-to-date
Huda Al-Taee
3 years ago
What is meant by bioavailability of a drug?
The extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action.
implementation of bioavailability on planning the dose of:
Cyclosporine
Absorption: only partially absorbed in the small intestine with large inter and intra-individual variability, peak concentration occurs after 1-8 hours.
Oral bioavailability is limited as a result of poor absorption, partial metabolism by enzymes in the gut, and first-pass hepatic metabolism. modified formulations lead to higher AUC.
The absorption and metabolism may vary with race and ethnicity with a lower rate among African-Americans.
Absorption is also dependent on bile salts, thus modified formulations are prefered in patients with biliary diversion or cholestasis.
Patients who are using cyclosporine ophthalmic emulsion have no significant systemic absorption.
Metabolism in the liver through cytochrome P-450, some metabolism occurs in the gut mucosa.
The cyclosporine metabolites have only 10-20% of the drug IS activity.
Interaction with food( grapefruit) and drugs.
Tacrolimus
Absorbed in the small intestine, oral bioavailability is limited ( 20%).
The oral bioavailability of extended-release tac is 50% higher as compared to the immediate-release formulation.
Extended-release tac formulations exhibit chronopharmacokinetic effects, evening administration compared with morning dosing results in 15% lower AUC for extended-release tac tablets and 35% lower AUC for extended-release tac capsules, thus both should be taken consistently every morning.
Extended-release tac capsules have AUC0-24 higher than that of immediate-release tac.
Tac absorption is lower in the African-American population may be due to the differences in the frequency of polymorphisms in the CYP3A5 gene.
Tac is minimally absorbed in patients with normal skin but significant absorption has been reported in patients with skin disease.
Metabolised extensively by cytochrome P-450 in the liver.
The metabolite of Tac possesses the same efficacy as the parent drug.
Interact with food ( grapefruit) and drugs.
Drugs that increase the concentration :
diltiazem, ketoconazole, erythromycin
Drugs that may lower tac concentration:
anticonvulsant and anti-TB
MMF
Bioavailability is 90% and significantly reduced when taken with a high-fat meal so it should be taken on an empty stomach and to improve GI tolerability, it may be taken with meals at consistent times each day.
Dose adjustment is required in severe chronic renal failure due to the prolongation of the half-life of MPAG.
Metabolised by cytochrome 3A4/5
Drug interaction:
Drugs that decrease MMF absorption:
antacids, mineral supplements, sevelamer, bile acid sequestrants, PPI, rifampicin
Drugs that increase MMF level;
acyclovir, valacyclovir, probenecid
Azathioprine
Absorbed from the gut. bioavailability varies greatly between individuals ( 30-90%)
References:
Chow ShCh. Bioavailability and Bioequivalence in Drug Development. Wiley Interdiscip Rev Comput Stat. 2014 ; 6(4): 304–312.
bioavailability is a measure of the rate and fraction of the initial dose of a drug that successfully reaches either; the site of action or the bodily fluid domain from which the drug’s intended targets have unimpeded access.
bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered.
What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
A -TACROLIMUS
Cytochrome P450 3A4 (CYP3A4) is the principal iso-enzyme responsible for the metabolism of tacrolimus
. Extrahepatic metabolism by CYP3A4 in the gastrointestinal epithelium is responsible for presystemic elimination of about half of the absorbed dose.
first-pass metabolism by CYP3A4 in the liver accounts for an additional 10% of elimination.
The extent of absorption of tacrolimus from the gastrointestinal tract is also influenced by the activity of P-glycoprotein (P-gp) in enterocytes., which explainis the high levels of tacloiums during diarheal episodes
Drug interactions with CNI
A- Enzyme inhibitors increase level of CNI:
CCB : verapamil, diltiazem, and amlodipine increase level of CNI.
Antifungal drugs : ketoconazole, fluconazole, and itraconazole increase level of CNI.
Antibiotics : erythromycin and clarithromycin increase level of CNI.
Grapefruit juice increase level of CNI.
B- Enzyme inducers decrease level of CNI:
Anticonvulsants : phenytoin, carbamazepine and phenobarbiturates decrease level of CNI.
Anti TB drugs : rifampin and INH decrease level of CNI.
B-MMF
MMF, being a pro-drug of MPA, is absorbed rapidly and completely from the gastrointestinal tract and undergoes extensive presystemic de-esterification to become MPA, the activemoiety.
MPA undergoes enterohepatic circulation; its plasma concentration profile shows a secondary peak at 6 to 12 h after intravenous or oral dosing. After an oral dose, MMF in the systemic circulation quickly disappears and the plasma concentration of MPA rises rapidly, reaching its maximum concentration within 1 h.
Food intake can delay the rate of MMF absorption but does not affect the extent. Co-administration of antacids or cholestyramine decreases the extent of absorption by approximately 20 and 40%, respectively .
therapeutic monitoring of MPA levels is available,but its role has not been established. May be measured in those with severe GI side effects.
C-CYLOSPORINE,
Concentrations of CsA in blood are significantly influenced by factors that alter its absorption. In healthy individuals, the oral bioavailability of CsA is low (about 30%) and quite variable due mainly to poor absorption from the small intestine.
CsA is extensively metabolized in the liver by P450 isozymes to relatively inactive hydroxylated and demethylated products.
CsA is subject to clinically important pharmacokinetic and pharmacodynamic drug interactions,drugs such as phenytoin , can reduce trough blood CsA concentrations to subtherapeutic levels whereas others, such as erythromycin, increase trough concentrations to potentially toxic levels.
D-AZATHIOPRINE,
The absorption of orally administered AZA is rapid. Peak plasma concentrations of 6MP, an intermediate metabolite of AZA, has been observed within 1-2 hour.
studies demonstrated that AZA is rapidly converted into 6MP.
doses are still based on body weight. Typically, patients undergoing renal transplantation do not receive more than 3 mg/kg orally except in the first few days after transplantion.
REFEERENCES
1-Nasrullah A. Undre.Pharmacokinetics of tacrolimus-based combination therapies.Nephrol Dial Transplant (2003) 18 [Suppl 1]: i12–i15.DOI: 10.1093/ndt/gfg1029.
2-Hyunyoung Jeong* and Bruce Kaplan†.Therapeutic Monitoring of Mycophenolate Mofetil.Clin J Am Soc Nephrol 2: 184 –191, 2007. doi: 10.2215/CJN.02860806.
3-D. J. FREEMAN.Pharmacology and Pharmacokinetics of Cyclosporine.Clin Biochern, Vol. 24, pp. 9-14, 1991.
4-Gary L. C. Chan, Pharm.D., Daniel M. Canafax, Pharm.D., and Curtis A. Johnson, Pharm.D.The Therapeutic Use of Azathioprine in RenalTransplantation.Pharmacotherapy 1987;7(5):165-77.doi: 10.1002/j.18759114.1987.tb04046.https://doi.org/10.1002/j.1875-9114.1987.tb04046.
Drug bioavailability:
The extent and rate at which the active moiety (drug or metabolites) enters systemic circulation,thereby accessing the site of action.This is always measured by Area under the concentration time curve AUC.
AUC:
The effect of a medicine is measured by quantifying AUC ,which is serum concentration vs time frame.
It’s largely dependent on the properties of the dosage form,which depend partly on its design and manufacture. Therefore rout of administration is pivotal in determining the concerned bioavailability,and subsequently the dosage of medicine.
Oral administration of medicine will be subjected to the absorption by intestinal wall to the portal circulation.
First pass metabolism:
Metabolism that occurs before a drug reaches systemic circulation. Therefore, many drugs may be metabolized before adequate plasma concentrations are reached.
Low bioavailability:
1) Extensive first pass metabism as mentioned earlier.
2) insufficient time for reabsorption.
3) Gastrointestinal disorders:Malabsorption syndrome,Achlorhydria,previous GI surgery.
4) chemical reactions,
Assessment of bioavailability:
Performed by determining the area under the plasma concentration-time curve AUC. Which is comparison of plasma level of a drug given by particular rout of administration with plasma level achieved by intravenous injection.
Bioavalability of Anti-rejection medications:
Cyclosporin:
Bioavailability of Cyclosporin is variable. Ranging from 10% to 89%. Peak bio-availability occurring 1-8 hours after administration.
Tacrolimus:
Bio-availability of Tacrolimus is poor, range from 11.2-19.1%, and it’s even worse in patient awaiting transplantation. Its peak level acheived within 1.5 -2 hours after adminstration.
MMF:
It’s bioavailability,94%.As it’s rapidly absorbed in the small intestine,It’s maximum concentration reached by 60-90 minutes..
Azathioprine:
It’s bioavalability is 50-60%
Implementation in Renal Transplantation:
1)As far as the bioavailability of CNI is poor ,especially for Tacrolimus, both of the CNI have to be administered intravenously in early pre and post transplantation to achieve a therapeutic level.
2) because of AUC spanning over few hours, 2 separate doses of CNI have to be administered.
3) Due to the variable range of intestinal absorption and therefore of AUC thereof,trough blood level has to be relied on in determining the dose of CNI.
4) The constant level of bioavailability and peak level of MMF , and make measurment of its trough level unnecessary in the daily practice. .
5) Similarly, MMF rapid absorption and peaking level ,make it mandatory to administered twice daily.
6) The same concerns applied to AZA,as it’s constantly absorbed with expected trough level and peak level..
References:
1)Gary price;Deven A.Patel.Drug bioavailability, September 2021 university of Tennnessee health science center.
2)Drug Bioavailability,Comprehensive Medical ChemistryII ,2007.
Bioavailability is a term that includes both the extent and rate of drug absorption . The extent of drug absorption (F) represents the fraction of the administered amount of drug that reaches the peripheral circulation in its active form.
Bioavailability of immunosuppressive drugs:
1-Mycophenolate mofetil (MMF, CellCept): Oral bioavailability :80.7% (renal transplant patients) 94% (healthy volunteers) *Effect of food in absorption: High-fat meal: ↓Cmax by 40%; AUC is unchanged -Should be taken on an empty stomach or at a consistent time each day in relation to meals to improve GI tolerability -Giving total daily dose in three or four equally divided doses may improve GI tolerability *Half-life in hours:17.9 (11.4 to 24.4)¶ (MPA): the inactive metabolite mycophenolic acid glucuronide MPAG can accumulate in renal failure. which is excreted primarily via urine 2-Mycophenolate sodium, enteric coated (Myfortic): Oral bioavailability: 72% (renal transplant patients) *Effect of food in absorption: High-fat meal: ↓Cmax by 33%; AUC is unchanged Should be taken on an empty stomach *Half-life in hours:12 (8 to 16) (MPA): the inactive metabolite mycophenolic acid glucuronide MPAG can accumulate in renal failure. which is excreted primarily via urine
3- Cyclosporine modified (microemulsion)(Neoral): Oral bioavailability 23 to 50% better absorbed than non-modified formulation (Cyclosporine non-modified (Sandimmune) 10 to 89%) (renal transplant patients) <10% (liver transplant patients) in renal and liver transplant patients, respectively *Effect of food in absorption: High-fat meal: ↓ Cmax by 33% and ↓AUC by 13% Should be taken at a consistent time each day in relation to meals *Half-life in hours:8.4 (5 to 18), Prolonged in hepatic impairment. inactive metabolites cleared fecally via bile 4-Tacrolimus immediate-release capsule (Prograf): Oral bioavailability: 7 to 32% *Effect of food in absorption: High-fat meal: ↓Cmax by 77% and ↓AUC by 37% High-carbohydrate meal: ↓Cmax by 65% and ↓AUC by 28%,Should be taken on an empty stomach
*Half-life in hours:12 (2 to 36), Prolonged in severe hepatic impairment, inactive metabolites cleared fecally via bile Tacrolimus extended-release capsule (Astagraf XL): Oral bioavailability: 12 to 19% *Half-life in hours: 38 (35 to 41),Prolonged in severe hepatic impairment
Bioavailability ; is simply the amount of drug reaching systemic circulation after its administration
Tacrolimus ;
Block signal 1 of T cell cell allorecogniztion
Therapeutic drug monitoring is essential due to narrow therapeutic index ; too little = inadequate immunosuppression , too much =side effects
Significant inter-patient variation in drug metabolism
Drug concentrations are measured in the whole blood, RBCs, or plasma protein bound
12 h trough level(C0) are generally measured and correlate well with drug exposure = advantage over cyclosporin
Dose ; 0.1 mg/kg in two divided doses or as single dose for once daily formulation, with subsequent adjustment according to level
Different formulations e.g. prograft twice daily, Advagraft once daily
Several new generic preparations are available with potentially significant differences in bio-availiability between brands
Metabolized by cytochrome P450(CY3A4) system with implications for drug interactions
If required IV, the dose is 0.003-0.05 mg/kg infusion over 24h
2.Ciclosporin ;
Neoral , micro-emulsion preparation has been the main cyclosporin formulation over recent years, but several generic preparations are now available.
There are important differences in bio-availability between formulations, so it is essential that the patient is consistently prescribed that brand
Dose; 7 mg/kg in two divided doses with subsequent adjustment according to the levels.
There has been much interest in using 2h post-dose level(C0) for therapeutic drug monitoring, as these provide a better estimate of drug exposure. In some studies this was associated with decreased acute rejection rate. It has not been adopted widely because it is less practice
Cyclosporin is metabolized in the GI tract and liver by cytochrome P450(CY3A4) with implications for drug interaction
If required IV, give 1/3 of the oral dose
3.MMF ;
Ester pro-drug of the active compound mycophenolic acid(MPA)
Reversible inhibitor of Inosine Monophosphate DeHydragenase(IMDH), a critical enyzyme in de novo purine nucteotide synthesis
Relatively few drug interactions; cyclosporin decreases entero-hepatic recirculation of MPA , so higher doses of MMF are required with cycloporin than tacrolimus
Initial dose; MMF 1g bd , other centers use 1.5 g bd for black recipient and subsequent dosing will dependent on local protocol, CNI levels, tolerability, toxicity such as myelo-suppression
There is very marked inpatient variability in plasma MPA levels
Therapeutic monitoring of MPA levels is available,but its role has not been established. May be measured in those with severe GI side effects
4.Azathioprine ;
Metabolized to a purine analouge = 6- thioguanine which competitively inhibit purine synthesis for RNA & DNA . This inhibit all cell replication and decrease T cell proliferation
Interactions ; allopurinol should be used with great caution with azathioprine beacuse AZA is metabolized by xanthine oxidase and potentiate myelo-suppression. Consider conversion to MMF
Patients with an inherited deficiency of the enzyme thiopurine-methyltransferase(TPMT) metabolize AZA slowly resulting in drug accumulation and myelo-suppression. If necessary patients can be screen for TPMT & the presence of genetic abnormality
Dose ; 1.5 – 2mg/kg once daily once daily. Reduce if WCC < 4 & stop if < 2
Drug level is not employed in clinical practice
Reference ; Hand book of Nephrology & Hypertension ; Simon Steddon & Neil Ashman
Bioavailability : Active content of a drug enter the body systemic circulation for pharmacokinetic reaction.
1) Cyclosporin
Take at a consistent time of the day (at 12-hour intervals).
Starting dose at 4 to 10 mg/kg/day orally in two divided doses.
Start at the lower end of the dosing range and make adjustments based upon therapeutic drug monitoring level.
Aiming 200 to 300 ng/mL in the first 3 months after transplantation then 50 to 150 ng/mL for subsequent months.
Tacrolimus
Tacrolimus immediate-release form should be taken at a consistent time of the day, 12 hour intervals on an empty stomach. The extended-release products should be taken at the same time of the day in the morning.
Tablet should not be chew, divide, or crush.
Starting dose at 0.1 to 0.2 mg/kg/day orally in two divided doses.
Start at the lower end of the dosing range and make adjustments base on serum drug level.
In patients who receive Thymoglobulin for induction therapy:
Aiming 7 to 10 ng/mL for the first month after transplantation then 3 to 7 ng/mL for subsequent months.
In patients who do not receive antilymphocyte-depleting agents for induction therapy:
Aiming 8 to 10 ng/mL for months 1 to 3 after transplantation then 3 to 7 ng/mL for subsequent months.
MMF
Mycophenolate mofetil (CellCept) and enteric-coated (delayed-release) mycophenolate sodium (Myfortic) are not equivalent. Mycophenolate mofetil 500 mg is considered equivalent to mycophenolate sodium 360 mg.
Mycophenolate mofetil:
Route : Oral, IV:
Dosage : 1 g (range: 500 mg to 1 g) twice daily as part of an appropriate combination regimen
( EMMC 1999; Hardinger 2021; KDIGO 2009; TMMRT 1996; manufacturer’s labeling).
Mycophenolate sodium, delayed release:
Route : Oral
Dosade : 720 mg (range: 360 to 720 mg) twice daily as part of an appropriate combination regimen
(Hardinger 2021; KDIGO 2009; Salvadori 2004).
Azathioprine
Route : Oral, IV.
Dosage : 1 to 2 mg/kg once daily as part of an appropriate combination regimen
(Cristelli 2013; Wüthrich 2000).
manufacturer’s labeling recommends up to 3 mg/kg once daily; some experts do not exceed 150 mg/day (Remuzzi 2007).
Bioavailability is drug amount which reach circulation
Cyclosporine 35-45%
Tacrolimus 25%
MMF 94 %
Bioavailability: amount of the drug that reach circulation unchanged in its active form
Oral Bioavailability = (AUCoral/ AUCintravenous) x 100%
Drugs Bioavailability ;
Cyclosporine :
Bioavailability is 35 to 45 % , max blood concentration after 2 hours
Steady state level in 1 or 2 months.
Primarily eliminated in stool and bile ,
Better on empty stomach .
Tacrolimus:
Bioavailability 25%
max blood concentration after 2 hours , Primarily eliminated in stool and bile
Better on empty stomach; before meals or after 2 hours
MMF: Bioavailability is 94 % ,An enteric coated of MMF that is absorbed only in small intestine(Myfortic) is available with peak concentration after 2-3 hours . Better on empty stomach.Enzyme inhibitors increase its level as ; erythromycine , grape fruit , antifungal, verapamil,
Azathioprine: Bioavailability 47% , max blood concentration after 1 to 2 hours , Primarily eliminated in urine , Better after meals.
Bioavailability of a drug is the amount of the drug that reaches the peripheral circulation unchanged in its active form
The oral bioavailability of a drug = AUC oral/ AUC intravenous x 100%
Bioavailability of an oral drug depends on:
1) Gastrointestinal transit rate
2) First-pass metabolism and/or excretion by the gut/liver.
What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
o Oral bioavailability: 30-45%, increases with time and reaches max concentration after 2 hr ((from here comes estimation of C2 level) and food decreases its absorption and hence better given on empty stomach
o Reaches a steady state in 4-8 weeks.
o Volume of distribution: 3-5 L/kg
o Primarily eliminated in bile and stool, only 6% in urine.
o Oral bioavailability: 25%, max blood concentration is reached in 1-3 hours . Food decreases absorption, hence better to be given on empty stomach
o Volume of distribution: 0.68 L/kg.
o Primarily eliminated in bile and stool. Diarrhea may lead to increased absorption from lower GI tract increasing drug exposure and resulting in toxic levels.
o It is a pro-drug with oral bioavailability: 94%, max blood concentration is reached in 2 hrs hours. However, a second peak occurs after 6-12 hours due to entero-hepatic circulation. Fatty diet decreases the absorption, so better given on empty stomach unless GIT side effects occur, so can be given during meals
o Volume of distribution: 0.71 L/kg. Eliminated in urine (93%).
o An enteric coated of MMF that is absorbed only in small intestine(Myfortic) is available with peak concentration after 2-3 hours. AUC of mycophenolic acid increases over time.
o Oral bioavailability is 47% , max blood concentration is reached in 1-2 hours. It is administered after meals to avoid GI side effects.
o Volume of distribution: 0.1 – 1.7 L/kg.
References:
1)Hand book of kidney transplantation 6th edition
2) Srinivas TR, Meier-Kriesche HU, Kaplan B. Pharmacokinetic principles of immunosuppressive drugs. Am J Transplant. 2005 Feb;5(2):207-17
What is meant by bioavailability of a drug? What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
Bioavailability refers to the percentage of the drug that reaches the blood stream, it is calculated by the area under the curve relating the dose given via different routes and the drug level in the blood over a period of time.
Drugs given via IV route have 100% bioavailability.
Cyclosporine bioavailability:
Food may decrease cyclosporine absorption.
It should be taken in the same time related to meals, either with or without.
There are different generic preparations with bioavailability differences between formulations.
Oral dose is usually 3 times of IV dose.
Ketoconazole is used to reduce the dose and the cost because it increases the blood level of cyclosporine.
There is inter patient variability in absorption and drug-drug interactions.
Tacrolimus Bioavailability:Food decreases absorption of tacrolimus by 30%, Tacrolimus should be taken on empty stomach 1hour before or 2 hours after meal.
There is intra-patient (effect of food, drug-drug interactions) and inter-patient variability (different activity of Cytochrome B450).
There is different formulation of Tacrolimus.
Oral dose is usually 3-5 times as IV dose.
CNIs drug interactions:
1- Enzyme inhibitors increase level of CNI:
Calcium Channel Blockers: verapamil, diltiazem, and amlodipine.
Antifungals: ketoconazole, fluconazole, and itraconazole.
Antibiotics : erythromycin and clarithromycin.
Grapefruit juice increase level of CNI.
2- Enzyme inducers decrease level of CNI:
Anti-epileptics: phenytoin, carbamazepine and phenobarbiturates.
Anti TB drugs : rifampin and INH.
Mycophenolate Bioavailability:
Can be taken with or without food.
Cyclosporine reduces the level of MMF, so the dose is usually higher (2gm daily) when MMF is combined with cyclosporine compared to when combined with tacrolimus (1 gm daily).
Proton pump inhibitors reduces MMF absorption. However, they don’t affect enteric coated- mycophenolate sodium.
Corticosteroids may lower the level of mycophenolic acid. Steroid free protocols use lower doses of MMF.
Aluminum or magnesium hydroxide antacids reduce absorption of MMF
Azathioprine Bioavailability:
It is a prodrug, 50-70% of the dose is absorbed and 88% is converted to 6- Mercaptopurine, it is usually taken with or without food.
TPMT activity should be checked before starting Azathioprine, recipients with deficiency of TPMT slowly metabolize Azathioprine, so they are liable to azathioprine accumulation and bone marrow suppression.
Bioavailability: amount of the drug that reach the circulation unchanged in its active form
Oral Bioavailability = (AUCoral/ AUCintravenous) x 100%
Factors affecting Oral bioavailability:
*GIT absorption
*first pass metabolism
Drugs ;
Cyclosporine :
Bioavailability is 35 to 45 % , max blood concentration after 2 hours (hence C2)
Steady state level in 1 or 2 months.
Volume of distribution 5L/kg
Primarily eliminated in feaces and bile
Better on empty stomach .
Tacrolimus:
Bioavailability 25%
max blood concentration after 2 hours
Volume of distribution 0.68L/kg
Primarily eliminated in feaces and bile
Better on empty stomach.
MMF:
Bioavailability is 94 % ,
max blood concentration after 2 hours
2nd peak in 6 to 12 hours.
Steady state level in 1 or 2 months.
Volume of distribution 0.71L/kg
Better on empty stomach . Avoid with fatty meals.
Azathioprine:
Bioavailability 47%
max blood concentration after 1 to 2 hours
Volume of distribution 0.1 to 1.1 L/kg
Primarily eliminated in urine
Better after meals.
☆Bioavailability of a drug:
_____________________________
Refers to the extent a substance or drug becomes completely available to its intended biological destination [1]
▪︎ It is a measure of how much a substance is able to access the circulation and reach the target area, and it depends on absorption (how much we get it) and secretion (how much we get out).
▪︎Bioavailability of a drug is largely determined by the properties of the dosage form, which depend partly on its design and manufacture. Differences in bioavailability among formulations of a given drug can have clinical significance; thus, knowing whether drug formulations are equivalent is essential.
☆Cyclosporine:
_________________
▪︎The bioavailability of cyclosporine is variable, ranging from less than 10% to 89% in various populations. As a result of its lipophilicity, cyclosporine is ⅞ distributed outside of the blood volume once it is absorbed. The volume of distribution ranges from 3 to 5 L/kg [2]
☆Oral bioavailability of tacrolimus:
_____________________________________
▪︎Vriable between patients, averages ;25%. This is largely due to extrahepatic metabolism of tacrolimus in the gastrointest
epithelium. Nevertheless, intra-patient variability is low, as evidenced by the small number of dose changes required to maintain patients within the recommended
tacrolimus target levels.
▪︎Tacrolimus is distributed extensively in the body with most partitioned outside
the blood compartment. Concentrations of tacrolimus in blood are used as a surrogate marker of clinically relevant concentration of the drug at the site(s) of action. Convenient whole-blood sampling within a
“2-h window around 12 h post-dose (Cmin) is highly predictive of systemic exposure to tacrolimus and is thus used to optimise therapy.
▪︎The interactions of tacrolimus with other immunosuppres-sive agents are well characterized.
☆MMF:
_________
▪︎Mycophenolate mofetil is rapidly absorbed in the small intestine.
▪︎The maximum concentration of its active metabolite, MPA, is attained 60 to 90 minutes following an oral dose. The average bioavailability of orally administered mycophenolate mofetil in a pharmacokinetic study is 94% [4].
☆Azathioprine:
__________________
▪︎Azathioprine is an immunosuppressive agent which functions through modulation of rac1 to induce T cell apoptosis, as well as other unknown immunosuppressive functions.
▪︎ It has a long duration of action as it is given daily, and has a narrow therapeutic index.
▪︎ Patients should be counselled regarding the risk of malignancies of the skin and lymphomas.
▪︎Mechanism of action: Is not entirely understood but it may be related to inhibition of purine synthesis, along with inhibition of B and T cells.
6-thioguanine triphosphate, a metabolite of azathioprine, modulates activation of rac1 when costimulated with CD28, inducing T cell apoptosis.
▪︎Humans Absorption
Oral azathioprine is well absorbed, with a Tmax of 1-2h.Further data regarding the absorption of azathioprine is not readily available.
▪︎Volume of distribution: Data regarding the volume of distribution of azathioprine is not readily available.
▪︎Protein binding: Azathioprine is 30%1bound to proteins such as human serum albumin in circulation.
▪︎Metabolism: Is converted to 6-mercaptopurine
▪︎The intestinal absorption of azathioprine ranges from 50 to 72% [5]
____________________
Ref:
[1] Price G, Patel DA. Drug Bioavailability
[2] Miles G. Choc. Bioavailability and pharmacokinetics of cyclosporine formulations: Neoral® vs Sandimmune®
. June 2008.
Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. Bioavailability of a drug is largely determined by the properties of the dosage form, which depend partly on its design and manufacture.
For intravenous route bioavailability is 100%, while in other routes of administration such as oral route it could be lower due to first pass effect.
Drug bioavailability after oral administration is affected by a number of different factors, including physicochemical properties of the drug, physiological aspects, the type of dosage form, food intake, biorhythms, and intra- and interindividual variability of the human population. Accordingly immunosuppressant agent should be monitored by assessing their blood level.
Cyclosporine:
Tacrolimus:
MMF:
Azathioprine:
References:
Bioavailability refers to the exact level of drug available in circulation for intended effects on target receptors after passing through different barriers . It can be affected by intrinsic or extrinsic factors like physical properties of drugs, dose, formulation and use of other medications or foods .It could be 100 % for IV route while significantly lower in oral route. The time taken-T max to achieve maximum drug concentration and the actual maximum drug concentration will depend on many factors and will be specific for each drug.
Cyclosporine
It can be given through IV and PO. Absorption can be affected by several factors including metabolism by CYP3A..Substances affecting cytochrome can affect Cyclosporine bioavailability. Peak bioavailability can be achieved in 1-8 hours. Almost 50 % can be bound to blood elements like RBC and lymphocytes. It has narrow therapeutic range and close monitoring of drug levels is needed. Significant drug interactions like phenytoin can reduce serum levels while erythromycin can increase the levels.
Tacrolimus.
It is metabolized by cytochrome CYp3A4/5 and can be given by PO and IV routes. The oral formulation is available as 0.5, 01 and 5 mg. It has narrow therapeutic index and bioavailability can be between 5-93%. PO is usually 3-4 times higher than IV dose. In the circulation it bind to proteins and RBCs. Peak level can be achieved in one hour. Metabolism can occur in intestine, liver and kidney. Bioavailability can be affected by multiple factors including diabetes, bowel resection , afro american or non white races.
Azathioprine.
It is an antimetabolite with narrow therapeutic range and bioavailability is around 50-70 % and metabolized in the liver. After PO administration the absorption is quick and peak plasma levels can be seen in 1-2 hours. It is distributed in body fluids except extracellular fluids. Its use should be avoided with allopurinol. Leukopenia can result if used with cotrimoxazole or ACE inhibitors. MMF replaced mostly.
MMF
It blocks the proliferation of Band T cells by reversibly inhibiting inosine monophosphate dehydrogenase and rapidly absorbed from gut and 90% is bound to plasma proteins. T max can be achieved in 1.5 hours. Absorption can be affected by antacids and cholestyramine. 93 % is excreted in urine. Its available in 250 mg immediate release form and 500 mg Tabs.
References
Handbook of kidney transplantation – Gabriel M Danovitch
Uptodate
▪︎What is meant by bioavailability of a drug?
Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action.
▪︎implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
●Cyclosporine
The bioavailability of cyclosporine is variable, ranging from less than 10% to 89% in various populations.
As a result of its lipophilicity, cyclosporine is largely distributed outside of the blood volume once it is absorbed. The volume of distribution ranges from 3 to 5 L/kg.
Cyclosporine is primarily metabolized through the cytochrome P-450 Ill-A enzyme system in the liver, intestine, and kidney.
At least 25 metabolites have been identified; however, the biologic activity and toxicity of these metabolites are considerably less than those of the parent compound. •
Both cyclosporine and its metabolites are excreted primarily in the bile, with only 6% of the dose eliminated itl the urine.
The eliminatioti half-life of the parent compound in the blood is =8 h.
Compared with Sandimmune, Neoral provides increased bioavailability as evident in increased area under the curve (AUC), increased peak blood concetitration and decreased time to peak blood concentration .
Neoral also provides a linear dose response over a wide dosage range, in contrast to Sandimmune.
Half-Life: 8.4 to 27 hours: The time to peak blood cyclosporine concentrations (Tmax) ranges from 1.5 to 2 hours.
Concomitant administration of Neoral with food causes a small (< 20%) but consistent decrease in bioavailability.
Dose usually divide every 12 hours.
●Tacrolimus
Tacrolimus is poorly bioavailable in patients awaiting renal transplantation (mean bioavailability of 14%, range 6–36%) .
This observation explains why tacrolimus is administered intravenously during the immediate postoperative period.
The low bioavailability of tacrolimus could be due to gut metabolism or to poor oral absorption of the drug.
metabolism by CYP3A4 in the liver accounts for an additional 10% of elimination.
Max blood concentration in 1-3 hours, Volume of distribution: 0.68 L/kg.
Primarily eliminated in bile/feces.
12 hour divided doses are usually used.
●MMF
Mycophenolate mofetil is rapidly absorbed in the small intestine, The maximum concentration of its active metabolite, MPA, is attained 60 to 90 minutes following an oral dose.
The volume of distribution of mycophenolate mofetil is 3.6 (±1.5) to 4.0 (±1.2) L/kg.
The protein binding of mycophenolic acid, the metabolite of mycophenolate mofetil, is 97% and it is mainly bound to albumin.
MPAG, the inactive metabolite, is 82% bound to plasma albumin at normal therapeutic concentrations. At elevated MPAG concentrations due to various reasons, including renal impairment, the binding of MPA may be decreased due to competition for binding
The average apparent half-life of mycophenolate mofetil is 17.9 (±6.5) hours after oral administration and 16.6 (±5.8) hours after intravenous administration.
cyclosporin but not tacrolimus decreases entero-hepatic recirculation of MPA , so higher doses of MMF are required with cycloporin.
●Azathioprine
Oral bioavailability 47% (27-80%).,Max blood concentration in 1-2 hours, Primarily eliminated in urine.
Azathioprine is immunosuppression if choice in pregnancy but not with lactation.
Allopurinol should be used with great caution with azathioprine because AZA is metabolized by xanthine oxidase and potentiate myelosuppression.
Reference
Bioavailability and pharmacokinetics of cyclosporine formulations: Neoral® vs Sandimmune® Miles G. Choc.
Marie Antignac, Benoit Barrou, and Saïk Urien
Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients.Br J Clin Pharmacol. 2007 Dec; 64(6): 750–757.
What is meant by bioavailability of a drug? What is the implementation of
bioavailability on planning the dose of the following immunosuppressive drugs?
Bioavailability:
Refers to the extent a substance or drug becomes completely available to its intended
biological destinations.
For majority purposes, bioavailability is defined as the fraction of the active form of a
drug that reaches systemic circulation unaltered.
The route of administration (ROA) and the dose of a drug have a significant impact on
both the rate and extent of bioavailability.
Concern issue:
Oral drugs, unlike drugs with other ROAs (i.e., IV drugs), must undergo intestinal
absorption and hepatic first-pass metabolism. A myriad of structural and physiological
gastrointestinal (GI) alterations such as GI surgery or chronic inflammatory intestinal
conditions affect this absorption, typically by reducing bioavailability.
Genetic polymorphisms of intestinal transporters that facilitate absorption (i.e., P-
glycoprotein 1) also affect drug bioavailability. Verapamil, a calcium channel blocker that
inhibits P-glycoprotein, has been shown to augment the plasma concentration of
immunosuppressive drugs that utilize P-glycoprotein in their elimination, such as
cyclosporine and tacrolimus, increasing the risk for toxicity.
Bioavailability of a drug will be reduced proportionally to the fraction of the initial dose
converted to inactive metabolites by liver enzymes.Notably, hepatic cytochrome P450
metabolism can significantly alter drug bioavailability. Cytochrome P450 enzymes can be
inhibited or augmented by a concurrent drug, supplement, or food metabolism.
Clinical significance:
Bioavailability of a drug can be influenced by both intrinsic and extrinsic variables.
Intrinsically:
Drug’s required metabolic steps to activation.
The specificity of its target receptors.
The patient’s unique physiology (including phenotypic polymorphisms).
Route of administration of the drug.
And site of drug absorption.
Extrinsic variables affecting drug bioavailability:
Include interactions with concurrent food or substance.
Metabolic processes.
Drug interactions with medications.
MMF:
80.7% (renal transplant patients) .
94% (healthy volunteers).
High-fat meal: ↓Cmax by 40%; AUC is unchanged.
Should be taken on an empty stomach or at a consistent time each day in relation to
meals to improve GI tolerability.
Giving total daily dose in three or four equally divided doses may improve GI tolerability.
MMF Enteric (myfortic).
72% (renal transplant patients.
§ High-fat meal: ↓Cmax by 33%; AUC is unchanged
§ Should be taken on an empty stomach.
Cyclosporine non-modified (Sandimmune):
Bioavailability:
Generally poor and unpredictable:
§ 10 to 89% (renal transplant patients)
§ <10% (liver transplant patients)
Effect of Food on absorption:
§ High-fat meal: ↓Cmax by 33%; AUC is unchanged
§ Should be taken on an empty stomach.
Cyclosporine modified (microemulsion) (Neoral):
Bioavailability:
23 to 50% better absorbed than non-modified formulation in renal and liver transplant patients, respectively.
Effect of Food on absorption:
§ High-fat meal: ↓Cmax by 33% and ↓AUC by 13%
§ Should be taken at a consistent time each day in relation to meals.
Tacrolimus immediate-release capsule (Prograf):
Bioavailability:
7 to 32%.
Effect of Food on absorption
§ High-fat meal: ↓Cmax by 77% and ↓AUC by 37%
§ High-carbohydrate meal: ↓Cmax by 65% and ↓AUC by 28%
§ Should be taken on an empty stomach.
§
Tacrolimus extended-release capsule (Astagraf XL):
Bioavailability:
12-19%.
Effect of Food on absorption:
§ High-fat meal: ↓Cmax by 77% and ↓AUC by 25%
§ Should be taken preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal.
AZA:
Hiopurine S-methyltransferase (TPMT) and/or nudix hydrolase 15 (nucleotide
diphosphatase; NUDT15) deficiency.
Patients with TPMT and/or NUDT15 deficiency, dosage reduction
Administering tablets after meals or in divided doses may decrease adverse GI events.
Reduce azathioprine dose to one third to one quarter of the usual dose if used with
allopurinol, and monitor closely for systemic toxicity
Bioavailability – refers to the percentage of active drug is found in plasma. Medication format (capsule, tablet, etc.), route of administration (oral, intravenous, topical), and other factors cause bioavailability to vary. So the effectiveness of a drug changes according to how it is administered, thus their serum concentrations must be measured.
Cyclosporine
– Its insoluble in water but soluble in organic solventes and lipids.
– Not significantly dialyzed – so during dialysis treatment not necessary dose adjustment
– Oral bioavailability is governed by absorption, gut metabolism by the isoenzymes of the cytochrome P-4503A (CYP3A) family
– Peak concentratrions in whole blood are attained 1 to 2 hours after oral administration;
– the bioavailability of the orally administred drug is in the range of 30% to 45%. And its increases with time, possibly as a resulto f P-gp inhibitory properties of the drug. As a result, the amount of cyclosporine required to achieve a given blood level tends to fall with time and typically reaches a steady level within 4 to 8 weeks.
– Practically insoluble in water, freely soluble in etanol and very soluble in metanol and chloroform
– Not significantly dialyzed – so during dialysis treatment not necessary dose adjustment
– Oral bioavailability is governed by absorption, gut metabolism by the isoenzymes of the cytochrome P-4503A (CYP3A) family. Gastrointestinal absorption is dependente on the presence of food, bile acids and motility.
– Peak concentratrions in whole blood are attained 1 to 2 hours after oral administration. If necessary the drug can be adminstered through a nasogastric tube or sublingually
– Low oral bioavailability – avarage 25%.
– Available in intravenous and capsules. The conversion is safe, but patients should be monitored closely during the process.
– Diarrhea may lead to increased absorption of tacrolimus from the lower GI tract with resultant toxic levels
– Mycophenolate mofetil is a prodrug to active compound of which is mycophenolic acid (MPA). Orally administered MMF is hydrolyzed to MPA, presystemically and is rapidyd absorbed, producing a peak level in approximately 1 hour.
– The bioavailability of MMF is roughly 90% with 97% of the MPA protein bound to albumin.
–
– Half of orally administered is absorbed, thus the intravenous dose is equivalente to Half the oral dose;
– The drug is not significantly dialyzed or excreted by the kidney
– Blood levels are not valuable clinically because its effectiveness is not blood-level dependente
– Regular monitoring of hematologic parameters is a importante aspect because marrow suppression.
– dose is 2.5mg/Kg/day when used alone. In triple protocolo or associated with steroids the dose is 1.5mgKg/day.
Bioavailability is the fraction or percent of a drug that enters systemic circulation in comparison with IV administration. So when a drug is administered IV, its bioavailability is 100% (f=1) which is different when it is administer via oral, subcutaneous sublingual, transdermal or rectal routs.
Factors that affect absorption such as concomitant use with food or other drugs or disease that influence liver metabolism or GI functions can alter bioavailability of a drug.
Cyclosporine:
The bioavailability of Neoral (the micro-emulsion formulation) is better and its peak levels (C2) is higher and co has better correlation with drug exposure.
Neural has lesser dependence of bile for absorption and has better GI absorption.
Bioavailability of the orally administered drug is between 30-40 % with conversion dose ratio of 3:1 between oral and IV forms.
Its bioavailability increases over time due to its p-glycoprotein inhibitor activity
So, to reach a steady level with fixed dose 4-8 week is needed.
Its volume of distribution is 3-5 Lit/kg, majority in RBC with high protein binding. Its half-life is between 6-27 h with 25% greater clearance in pre-pubertal ones.
The majority of drug is excreted in the bile and less than 6% in the urine and 0.1 unchanged .
Tacrolimus:
It is not dependent on bile for absorption and oral bioavailability is limited (20%) due to poor absorption, bowel mucosa causing partial metabolism and first-pass hepatic metabolism. The bioavailability of extended release tacrolimus is almost 50% higher than immediate –release.
There are inter and metabolism of CNIs.
There absorption is decreased with a fatty meal. Tacrolimus is taken up by erythrocytes and binds to proteins (albumin and α1-acid glycoprotein).
Their metabolism is through cytochrome p-450 CYP3A in the liver and gut mucosa and drugs that inhibit or induce their activity can increase or decrease their blood levels respectively.
MMF: oral MMF is hydrolyzed to mycophenolic acid and peak in about one hour.
The bioavailability of MMF is rough 90%.
The majority of MPA bound to albumin.
Enteric coated MPA only dissolves in the intestine with neutral PH and peaks after 2-3 hours.
Its AUC increase with time, MPA is glucuronidated to MPAG which has enterohepatic cycling causing a second peak at 6-12 hours.
Its half is about 6-18 hours.
Azathioprine (Imuran): It is an antimetabolite and can be used in pregnancy.
The bioavailability of orally administered azathioprine, comparing to IV dose is about 50%.
As an adjunction therapy with CNI its dose is 1-2 mg/kg
Bioavailability is a key indicator of drug absorption. It represents the administered dose fraction which achieves success in reaching the systemic circulation when administered orally or through any other extravascular dosing route.
Cyclosporine. It is a lipophilic molecule, with its bioavailability dependent on food, bile and other interacting factors.
Is extensively metabolized in the liver by the cytochrome P450 3A system.
Distribution depends on physicochemical, biological carriers such as lipoproteins and erythrocytes in blood. The distribution of metabolites in the body can differ from that of cyclosporine itself.
Elimination of the drug is mainly via the bile as metabolites, to lesser extent through the kidney
Pharmacokinetic parameters of cyclosporine are highly variable and depend on factors such as age, the physical condition of the patient, type of organ transplant.
Renal side effects of cyclosporine are dose-related. The therapeutic range and dosage of cyclosporine are therefore highly dependent on many individual parameters in patients. Dosages of less than 5 mg/kg/day, however, rarely cause renal side effects. Further studies to correlate the clinical pharmacokinetics of metabolites with their activity and adverse effects are needed.
Following oral administration, the absorption of cyclosporine is slow and incomplete. Peak concentrations in blood or plasma are reached in 1 to 8 hours after dosing. The bioavailability of cyclosporine ranges from less than 5% to 89% in transplant patients; poor absorption has frequently been observed in liver and kidney transplant patients and in bone marrow recipients. Factors that affect the oral absorption of cyclosporine include the elapsed time after surgery, the dose administered, gastrointestinal dysfunction, external bile drainage, liver disease, and food.
Tacrolimus is Tacrolimus is primarily metabolized by the cytochrome P450 system of liver enzymes, and there are many substances that interact with this system and induce or inhibit the system’s metabolic activity.
Interactions include that with grapefruit which increases tacrolimus plasma concentrations., the most commonly reported interactions include interactions with anti-microbial drugs. Macrolide antibiotics including erythromycin and clarithromycin, as well as several of the newer classes of antifungals, especially of the azole class (fluconazole, voriconazole), increase tacrolimus levels by competing for cytochrome enzymes.
The half-life is 12 hours and the total body clearance based on blood concentration is approximately 0.06 L/h/kg. The elimination of tacrolimus is decreased in the presence of liver impairment and in the presence of several drugs. Various factors that contribute to the large inter- and interindividual variability in the pharmacokinetics of tacrolimus are reviewed here. Because of this variability, the narrow therapeutic index of tacrolimus, and the potential for several drug interactions, monitoring of tacrolimus blood concentrations is useful for optimization of therapy and dosage regimen design.
Oral tacrolimus is slowly absorbed in the gastrointestinal tract, with a total bioavailability of 20 to 25% (but with variations from 5 to 67%) and highest blood plasma concentrations reached after one to three hours. Taking the drug together with a meal, especially one rich in fat, slows down resorption and reduces bioavailability.
MMF itself is not pharmacologically active: once MMF is absorbed, it is metabolized to mycophenolic acid (MPA), the major active metabolite.
When cyclosporine is coadministered with MMF in transplant patients, the plasma concentration or exposure of MPA is reduced [and MPAG concentration increased compared with patients receiving MMF plus tacrolimus or MMF plus sirolimus The differences in MPA concentration between these regimens have been attributed to the pharmacokinetic interaction between MPA and cyclosporine.
oral bioavailability: 94%.
· Max blood concentration in 1 ½ hour, second peak 6-12 hours later due to enterohepatic circulation ·
Volume of distribution: 0.71 L/kg. Primarily eliminated in urine (93%).
· absorbed only in the small intestine, with peak concentration after 2-3 hours.
Azathioprine: Oral bioavailability 47% (27-80%).
• Max blood concentration in 1-2 hours.
• Dose:2mg/kg as a single dose not divided
• Volume of distribution: 0.1 – 1.7 L/kg.
• Primarily eliminated in urine.
• Azathioprine is safe in pregnancy as The fetus does not have the liver enzyme to do that BUT after birth, his liver becomes mature and able to metabolize it so its better to stop AZA after delivery if she tends to breastfeed.
• Allopurinol should be used with great caution with azathioprine because AZA is metabolized by xanthine oxidase and potentiate myelosuppression.
• Genetic polymorphisms of certain enzymes play an important role in the metabolism of azathioprine, namely thiopurine S-methyltransferase (TPMT) and nucleoside triphosphate diphosphatase (NUD15). The deficiency of TPMT can cause the accumulation of 6-thioguanine nucleotides and 6-methylmercaptopurine, leading to hematological toxicity and hepatotoxicity.
# What is meant by bioavailability of a drug?
What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
# Cyclosporine
# Tacrolimus
# MMF
# Azathioprine
** Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action.
Bioavailability of a drug is largely determined by the properties of the dosage form, which depend partly on its design and manufacture.
** CYCLOSPORINE:
# The absorption of cyclosporine occurs mainly in the intestine, and is highly variable
# Bioavailability of 30% sometimes occurring 1-8 hours after administration with a second peak observed in certain patients.
# T- max :higher Tmax and a 59% higher Cmax with a 29 % higher bioavailability
# Volume of distribution:
The distribution in the blood consists of 33%-47% in plasma, 4%-9% in the lymphocytes, 5%-12% in the granulocytes, and 41%-58% in the erythrocytes
# Protein binding: About 50% of the administered dose is taken up by erythrocytes while about 34% is bound to lipoproteins,Prescribing information for Sandimmune states that 90% is mainly bound to lipoproteins.
#Metabolism: Cyclosporine is metabolized in the intestine and the liver by CYP450 enzymes, predominantly CYP3A4 with contributions from CYP3A5. Cyclosporine undergoes several metabolic pathways and about 25 different metabolites have been
identified.
# Elimination:
primarily biliary with only 3-6% excreted in the urine while 90% in the bile.1% unchanged
# The half life: of cyclosporine is biphasic and very variable on different conditions last 19 hours a range between (10 – 27 ) hours
# Common adverse effects are hypertrichosis, gingival hyperplasia, hyperlipidemia and nephrotoxicity,nausea, flushing, tremor, vertigo and vomiting, anorexia and a feeling of increased body girth.
** TACROLIMUS:
#Resorption (poor) throughout the gastrointestinal tract.
# The bioavailability is : 20 – 25%
# T max is : 1 – 3 hours (capsules and granules or 6 hours(tablets)
# Volume of distribution is : 0.68 l/kg
# Protein bound fraction is more than 99%
Metabolsim : CYP3A4- mediated metabolism in liver and intestinal epithelium
# Elimination is : 95 % with faeces
# Elimination half-life : 12- 15 hours
# Common adverse effects: Hypertension
diarrhoea, hyperglycaemia, anaemia, headache, tremor, insomnia
** MMF
# Rapidly converted to mycophenolic acid by plasma esterase, resorption throughout gastrointestinal tract.
# The bioavailability is : 94%
# T max is : 1.5 hour and a second peak between 6 – 12 hours owing to enterohepatic circulation.
# Volume of distribution is : 0.71 l/kg
# Protein bound fraction is 97%
Metabolsim : conversion to inactive glucuronide metabolite in liver
# Elimination is : 93% in urine, the remaining with faeces
# Elimination half-life : 12- 18 hours
# Common adverse effects:
diarrhoea, nausea, vomiting, leukopenia, anaemia, increase in blood creatinine, CMV viraemia, UTI, RTI and hepatitis
** AZATHIOPRINE
# Highly variable resorption throughout gastrointestinal tract.
The bioavailability is : 47%(27-80%)
# T max is : 1-2 hours
# Volume of distribution is : 0.1- 1.7 l/kg
# Protein bound fraction is 20 – 30 %
Metabolsim : rapid conversion in to 6 – mercaptopurine(a process that is partially dependent on TPMT)
# Elimination is : mainly with urine ,(as inactive thio-uricacid) small fraction eliminated with faeces
# Elimination half-life : 60 – 120 minutes(after conversion to 6 – mercaptopurine)
# Common adverse effects:
Nausea, vomiting, hepatic dysfunction, infection(viral, fungal, bacterial) and anorexia.
In pharmacology, bioavailability ( f ) is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100
order to determine absolute bioavailability of a drug, a pharmacokinetic study must be done to obtain a plasma drug concentration vs time plot for the drug after both intravenous (iv) and non-intravenous( i.e., oral) administration. The absolute bioavailability is the dose-corrected area under curve (AUC) non-intravenous divided by AUC intravenous.
f = 100 *( AUC po * D iv / AUC iv * D po )
f : bioavailability
D dose
Therefore, a drug given by the intravenous route will have an absolute bioavailability of 100% (f = 1), whereas drugs given by other routes usually have an absolute bioavailability of less than one
Cyclosporin
Tthe bioavailability of the orally administered drug is in the range of 30% to 45%. Conversion between the oral and intravenous forms of the drug perioperatively requires a 3:1 dose ratio and is administered twice daily as 4-hour infusions .
foods and drugs can affect its bioavailability.
tacrolimus
Despite its relatively poor bioavailability, it is rarely necessary to use the intravenous
formulation. If necessary, the drug can be administered through a nasogastric tube or sublingually. Intravenous dosing is approximately one-third of the total daily dose required by the oral route and is administered via a 24-hour continuous infusion. Sublingual dosing is more variable, but is usually one-half that required by the oral route.
With the immediate-release dosage forms, it is absorbed primarily from the small intestine, and its oral bioavailability is about 25%,with large interpatient and intrapatient variability .
MMF
both MMf ( CellCept ) and EC MPA ( Myfortic ) have Mycophnolic acid MPA as the active compound
The bioavailability of MMF is roughly 90%, with 97% of the MPA protein bound to albumin . the AUC of MPA increases with time; the same doses when used early postoperatively can produce much higher concentrations several months later. Patients should be continuously for adverse side effects and periodically be evaluated for an
MPA dose reduction, if clinically appropriate
Azathioprine
About half of orally administered azathioprine is absorbed; thus, the intravenous dose is equivalent to half the oral dose .
Blood levels are not valuable clinically because its effectiveness is not blood-level dependent.
references
What is meant by the bioavailability of a drug?
Bioavailability means the proportion that reaches the peripheral circulation active and unchanged after intake.
Oral Bioavailability = (AUCoral/ AUCintravenous) x 100%
Factors affecting bioavailability
1. GIT absorption
2. Rate of transit
3. GIT excretion and liver elimination
What is the implementation of bioavailability in planning the dose of the following immunosuppressive drugs?
Cyclosporine:
• Oral bioavailability: 30-45%,
• first-pass metabolism by CYP3A4 in the liver so any drug inhibits CYP3A4 (increase the cyclosporin level and vice versa)
• The absorption from the gastrointestinal tract is also influenced by the activity of P-glycoprotein (P-gp) in enterocytes which has an inhibitory effect (responsible for efflux of cyclosporine in gut lumen)
• steady state achieved in 4-8 weeks.
• Less dependence on bile for absorption with the microemulsion form but Food decreases absorption.
• Max blood concentration in 2 hours, Volume of distribution: 3-5 L/kg.
• Primarily eliminated in bile/feces, only 6% in urine(no change in dose-related to advanced kidney disease).
• Starting Dose has very wide from center to another usually 4-8mg/kg >>our center experience is to start with high dose(6mg/kg if the patient didn’t receive induction therapy), follow up is by trough level which also center-based and change regarding the duration of transplantation
Tacrolimus:
· Oral bioavailability: 25%.
· Dose: wide range from 0.1-0.2 >> our center usually use a higher dose in thin patients, pediatrics, and patients who didn’t receive any kind of induction
· first-pass metabolism by CYP3A4 in the liver accounts for an additional 10% of elimination.
· The extent of absorption of tacrolimus from the gastrointestinal tract is also influenced by the activity of P-glycoprotein (P-gp) in enterocytes., which explains the high levels of tacrolimus during diarrheal episodes
· Max blood concentration in 1-3 hours, Volume of distribution: 0.68 L/kg. Primarily eliminated in bile/feces.
· fast metabolizer: drug level/ the dose of tacrolimus used was < 1, and need higher doses of tacrolimus and is at higher risk of rejection.
MMF(Cellcept):
· oral bioavailability: 94%.
· Max blood concentration in 1 ½ hour, second peak 6-12 hours later due to enterohepatic circulation (that’s why to trough level doesn’t correlate with the AUC)
· Volume of distribution: 0.71 L/kg. Primarily eliminated in urine (93%).
Enteric-coated MMF (MPA >>Myfortic)
· absorbed only in the small intestine, with peak concentration after 2-3 hours.
· Dosing: in body weight below 40kg>23mg/kg/12h, above 40kg >>2gm/day independent of body weight and also dose change with the duration of transplantation and according to CBC
· Monitoring of AUC is not routinely done but some time is needed( if the patient is presented with recurrent infections and leucopenia after exclusion of CMV hematological manifestations)
· MMF inhibit Donovo pathway only for purine synthesis in lymphocytes And T and B lymphocytes(other cells have salvage pathway) solely on this pathway for the production of guanosine nucleotides
Azathioprine: Oral bioavailability 47% (27-80%).
• Max blood concentration in 1-2 hours.
• Dose:2mg/kg as a single dose not divided
• Volume of distribution: 0.1 – 1.7 L/kg.
• Primarily eliminated in urine.
• Azathioprine is safe in pregnancy as The fetus does not have the liver enzyme to do that BUT after birth, his liver becomes mature and able to metabolize it so its better to stop AZA after delivery if she tends to breastfeed.
• Allopurinol should be used with great caution with azathioprine because AZA is metabolized by xanthine oxidase and potentiate myelosuppression.
• Genetic polymorphisms of certain enzymes play an important role in the metabolism of azathioprine, namely thiopurine S-methyltransferase (TPMT) and nucleoside triphosphate diphosphatase (NUD15). The deficiency of TPMT can cause the accumulation of 6-thioguanine nucleotides and 6-methylmercaptopurine, leading to hematological toxicity and hepatotoxicity.
Bioavailability refers to the extent a substance or drug becomes completely available to its intended biological destination(s).
Bioavailability is expressed as the percentage of the total drug dose administered that reaches the circulation. For a drug taken orally, the ‘first-pass effect’ of hepatic metabolism reduces bioavailability. The bioavailability calculations include both free and bound forms of the drug. A systemic drug with a relatively low bioavailability is acyclovir; the prodrug for acyclovir, valacyclovir, has at least three times greater bioavailability. At the other end of the spectrum are the fluoroquinolones, for which oral absorption (and resultant bioavailability) is so complete that the oral and intravenous doses for many members of this drug group are identical.
1 Ciclosporin
Oral bioavailability: 30-45% . reach max concentration in 2 hours . Absorption decrease with meal . excreted mainly in feaces and small amount by kidneys. Drugs which inhibit the P glycoprotein will increase the systemic concentration of the CYC. For example diltiazem and verapamil inhibit the p Efflux glycoprotein and increase the levels of CYC in the blood. Drugs like Rifampicin can induce the P efflux glycoprotein and decrease the bio availability of the drug.
I think while prescribing we should keep in mind the fact that certain factors can decrease the bioavailability like pregnancy so dose is adjusted accordingly.
2.Tacrolimus
Oral bioavailability is highly variable and ranges from 5 to 93%. No dependence on bile for absorption. Max blood concentration in 1-3 hours, Food decreases absorption, It is metabolized by the enzyme CYP3A5. Pharmacogenetics have divided patients into poor and extensive metabolizers based on CYP3A5 genotyoe analysis. It is primarily eliminated in bile/ faeces. Diarrhea may lead to increased absorption from lower GI tract, causing toxic levels.
3.MMF
It is a prodrug with oral bioavailability: 94%. Max blood concentration in 1 ½ hours, second peak 6-12 hours later due to enterohepatic circulation. MMF is mainly eliminated in urine (93%). Enteric coated MMF absorbed only in small intestine, with peak concentration after 2-3 hours.If taken with food the bioavailability will decrease so better to be taken empty stomach though patients find it but difficult.
4. Azathiprine
The bioavailability of AzA is 16-50% with predominant hepatic metabolism, elimination half life 1-2 hours. Mainly eliminated in urine. It is administered after meals to avoid GI side effects.
While prescribing these immunosuppressive drugs we should keep in mind the factors affecting bioavailability
Is the drug given IV or oral
With food or empty stomach
Any associated drug affecting bioavailability
Age of patient
Effect of pregnancy on bioavailability
Effect of p glycoprotein
Enzyme CYP3A5
Inter patient variability
Any associated disease like liver disease
Etc
Bioavailability of a drug means the proportion of the drug which reaches the peripheral circulation and site of action unchanged after getting absorbed.
Bioavailability of an oral drug is calculated by comparing the AUC of the unmetabolized drug after intravenous and oral administration.
Bioavailability depends on the physio chemical barriers in the gastro intestinal mucosa, gastro intestinal transit rate and it depends on the pre systemic/first pass metabolism of drugs like MMF
Although many of the drugs are to be recommended to be given in empty stomach, many patients do not tolerate it when taken before food. To be consistent in the drug and achieving their drug levels, we can ensure that they are taken in a particular time of the day.
Bioavailability is percentage of drug that reaches systemic circulation unchanged form
It includes both the extent and rate of drug absorption.
The extent of drug absorption represents the fraction of the administered amount of drug that reach peripheral circulation in its active form. Bioavailability of an oral drug is calculated by comparing the AUC (area under the curve).The oral bioavailability of a drug can be defined as:
Oral Bioavailability = (AUCoral/ AUCintravenous) x 100%
Bioavailability of drugs administered orally is determined physiochemical barriers to absorption as gastrointestinal mucus membranes, pre systemic metabolism and/or excretion by gut or liver.
What is the implementation of bioavailability of planning the dose of the following immunosuppressive drugs?
Cyclosporine :Bioavailability(oral) is 30-68% with half life of 5-18 hours. The original formulation of cyclosporine, the oil-based Sandimmune, has largely been replaced by the microemulsion formulation, (Neoral) which is better than that of Sandimmune, and have less variability in cyclosporine pharmacokinetics and also less dependent on bile for absorption. Conversion between the oral and intravenous forms of the drug peri-operatively require a 3:1 dose ratio and is administered twice daily as 4-hour infusions.
The dose is 3-5mg/Kg twice daily. Primarily eliminated in bile/ faeces, only 6% in the urine. Food decreases absorption, hence better to give an empty stomach. Primarily eliminated in bile/ feces. Diarrhea may lead to increased absorption from the lower GI tract, causing toxic levels.
Tacrolimus: Bioavailability is 20-25% with half -life of 12-15 hours.The dose is 0.15-0.3mg/Kg twice daily. Food decreases absorption, hence better to give an empty stomach. Primarily eliminated in bile/ feces. Diarrhea may lead to increased absorption from the lower GI tract, causing toxic levels
Tacrolimus and cyclosporine are metabolized through CYP3A enzyme system
Liver dysfunction prolongs the half-life of both drugs. Food decreases CNI absorption
12 -hour trough level is used for monitoring drug level, dose changes are reflected in 2-3 days.
Ciclosporin trough level-(200-300ng/ml) in the first 03 months after transplantation
-50-150 ng/ml for subsequent months
Tacrolimus trough level- 7-10 ng/ml in 01 to 03 months after transplantation
3-7ng/ml for subsequent months
MMF–Prodrug converted to an active metabolite (mycophenolic acid), oral bioavailability is 94%.Max blood concentration in 1 ½ hour, second peak 6-12 hours later due to enterohepatic circulation. Primarily eliminated in urine (93%).The dose of Cellcept is 1gm twice daily.The dose of Myfortic is 720mg twice daily. The bioavailability of the drug gets reduced with high-fat diet, hence better to take an empty stomach to increase absorption. Cyclosporine decreases the level of MMF, so the recommended dose of MMF when used with cyclosporine is 2 gm, while when used with tacrolimus the dose can be reduced to 1 gm daily
Azathioprine: Analogue of 6 mercaptopurine and bioavailability is 16-50% with predominant hepatic metabolism, elimination half life 1-2 hours. Primarily eliminated in urine. It is administered after meals to avoid GI side effects.The dose is 3-5 mg/kg/day IV/PO initially on the day of transplant than a dose of 1-3 mg/kg/day IV/PO. Deficiency of enzyme TPMT can cause accumulation of 6-methylmercaptopurine leading to hepatotoxicity. Xanthine oxidase inhibitors should be avoided with azathioprine as increase the risk of accumulation of 6-mercaptopurine with consequent serious toxicity.
REFERENCES:
1-Srinivas TR, Meier-Kriesche HU, Kaplan B. Pharmacokinetic principles of immunosuppressive drugs. Am J Transplant. 2005 Feb;5(2):207-17.
2- Danovitch G.M handbook of kidney transplantation sixth edition
Bioavailability is the proportion of an administered dose of a drug that reaches the systemic circulation as intact drug . As an i.v. dose is injected directly into the systemic circulation, the bioavailability of an i.v. dose is by definition 100 percent
Cyclosporine: Oral bioavailability: 30-45% . reach max concentration in 2 hours . Absorption decrease with meal . excreted mainly on fesses and small amount by kidneys
· Tacrolimus: Oral bioavailability: 25%. reach max concentration in circulation 1-3 hours, . absorption decrease with meals, so better to give it in empty stomach.excreted on faeces. Diarrhea may lead to increased TAC blood level .
· MMF: oral bioavailability: 94% .excreted mainly in urine. Enteric coated MMF absorbed only in small intestine, with peak concentration after 2-3 hours .better In empty stomach .
· Azathioprine: Oral bioavailability: 47% .reach max concentration in circulation in 1-2 hours. Excreted mainly in urine
Bioavailability is percentage of drug that reach systemic circulation unchanged form
It includes both the extent and rate of drug absorption.
The extent of drug absorption represent the fraction of the administered amount of drug that reach peripheral circulation in its active form.
Bioavailability of drugs administered orally is determined by physiochemical barriers to absorption as gastrointestinal mucus membranes, pre systemic metabolism and/or excretion by gut or liver.
Bioavailability is 30-68% with half life of 5-18 hours
The dose is 3-5mg/Kg twice daily
Bioavailability is 20-25% with half life of 12-15 hours
The dose is 0.15-0.3mg/Kg twice daily
Tacrolimus and cyclosporine are metabolized through CYP3A enzyme system
Suboptimal bioavailability of is due to poor intestinal absorption, partial enzymatic metabolism in gastrointestinal mucosa and first pass hepatic metabolism.
Liver dysfunction prolong the half life of both drugs
12 hour trough level is used for monitoring drug level, dose changes are reflected in 2-3 days.
Prodrug converted to active metabolite (mycophenolic acid), oral bioavailability is 94% with half life of 17.9+/-6.5 hours
The metabolism is hepatic and enter enterohepatic circulation
The dose of Cellcept is 1gm twice daily
The dose of Myfortic is 720mg twice daily
Analogue of 6 mercaptopurine
Bioavailability is 16-50% with predominant hepatic metabolism
elimination half life 1-2 hours
the dose is 1-2mg/kg when used as adjunctive with CNI
Deficiency of enzyme TPMT can cause accumulation of 6-methylmercaptopurine leading to hepatotoxicity
Xanthine oxidase inhibitors should be avoided with azathioprine as increase the risk of accumulation of 6-mercaptopurine with consequent serious toxicity.
Srinivas TR, Meier‐Kriesche HU, Kaplan B. Pharmacokinetic principles of immunosuppressive drugs. American Journal of transplantation. 2005 Feb;5(2):207-17.
Kant S, Kronbichler A, Geetha D. Principles of Immunosuppression in the Management of Kidney Disease: Core Curriculum 2022. American Journal of Kidney Diseases. 2022 Apr 16.
Danovitch GM, editor. Handbook of kidney transplantation. Lippincott Williams & Wilkins; 2009 Oct 1.
Bioavailability
Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action.
Bioavailability of a drug is largely determined by the properties of the dosage form, which depend partly on its design and manufacture. Differences in bioavailability among formulations of a given drug can have clinical significance; thus, knowing whether drug formulations are equivalent is essential.
Cyclosporine and Tacrolimus
Absorption —
Cyclosporine and tacrolimus are absorbed in the small intestine, and peak blood concentrations occur after one to eight hours. The oral bioavailability is limited for both drugs (roughly 20 percent for tacrolimus) as a result of poor absorption, partial metabolism by enzymes in the bowel mucosa, and first-pass hepatic metabolism
modified formulations of cyclosporine lead to higher area under the time concentration curve (AUC) than the nonmodified preparations.
oral bioavailability of extended-release tacrolimus tablets was approximately 50 percent higher as compared with tacrolimus immediate-release at steady state
Both extended-release tacrolimus products exhibit chronopharmacokinetic effects; evening administration, compared with morning dosing, results in a 15 percent lower AUC for extended-release tacrolimus tablets and a 35 percent lower AUC for extended-release tacrolimus capsules Thus, both products should be taken consistently every morning.
The absorption and metabolism of calcineurin inhibitors may vary with race and ethnicity.
the mean tacrolimus exposure after a single 5 mg oral dose in healthy Hispanic and African-American individuals was 18 and 39 percent less, respectively, than in White individuals
Similar results have been seen with the extended-release products
Such variation may be related to differences in the frequency of polymorphisms in the CYP3A5 gene among African-American, Hispanic, and White transplant recipients
The absorption of cyclosporine, but not tacrolimus, is dependent upon bile salts. Thus, cyclosporine modified or tacrolimus may be preferable in patients with biliary diversion or cholestasis. Cyclosporine modified absorption is decreased modestly when ingested with a fatty meal
Similarly, tacrolimus absorption is decreased if administered after a fatty meal and should be taken on an empty stomach, if possible
Distribution —
Cyclosporine and tacrolimus are lipophilic and undergo extensive body distribution. In the blood, most of the absorbed amount of each drug is taken up by erythrocytes. In the plasma, cyclosporine binds mainly to lipoproteins, whereas tacrolimus binds to proteins, primarily albumin and alpha-1-acid glycoprotein.
Metabolism —
Cyclosporine and tacrolimus are extensively metabolized by cytochrome P-450 CYP3A enzymes in the liver. There is also some metabolism in the gut mucosa. The most active cyclosporine metabolites have only 10 to 20 percent of the drug’s immunosuppressive activity. By comparison, one of the metabolites of tacrolimus possesses equal immunosuppressive potency to the parent drug.
Elimination —
Cyclosporine and tacrolimus are excreted in the bile. The elimination half-life can vary significantly among patients, is approximately 19 hours for cyclosporine modified and 12 hours for immediate-release tacrolimus.
Food and drug interactions
Grapefruit or grapefruit juice can result in an increase in systemic exposure to cyclosporine or tacrolimus
Drugs
Macrolides
macrolides for respiratory tract infections: acute cyclosporine/tacrolimus toxicity may occur
Azathioprine
Azathioprine (Imuran) is an antimetabolite, an imidazole derivative of 6-mercaptopurine. It has been used in clinical transplantation for nearly 50 years. When cyclosporine was introduced, the role of azathioprine was largely relegated to that of an adjunctive agent, and with the introduction of MMF, its use has been discontinued in many programs. It can still be useful in certain circumstances and can be a valuable component of a low-cost immunosuppressive regimen
Mechanism of Action.
Azathioprine is a purine analogue that is incorporated into cellular deoxyribonucleic acid (DNA), where it inhibits purine nucleotide synthesis and interferes with the synthesis and metabolism of ribonucleic acid (RNA)
It is ineffective in the therapy of rejection episodes.
About half of orally administered azathioprine is absorbed; thus, the intravenous dose is equivalent to half the oral dose. Blood levels are not valuable clinically because its effectiveness is not blood-level dependent. The drug is not significantly dialyzed or excreted by the kidney. Dose reduction is often practiced during kidney dysfunction, although it may not be necessary. When used as the primary immunosuppressant, the daily oral dose is 2 to 3 mg/kg. When used as adjunctive therapy with a CNI, the dose is 1 to 2 mg/kg.
The azathioprine dose is usually reduced or stopped during episodes of significant hepatic dysfunction.
Mycophenolic Acid
Mechanism of Action.
MPA is a reversible inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH). IMPDH is a critical, rate-limiting enzyme in the so-called de novosynthesis of purines and catalyzes the formation of guanosine nucleotides from inosine.
Absorption and Distribution
Absorption and Distribution The pharmacokinetics of MPA is complex. Orally administered MMF is hydrolyzed to MPA presystemically and is rapidly absorbed, producing a peak level in approximately 1 hour. The bioavailability of MMF is roughly 90%, with 97% of the MPA protein bound to albumin. Orally administered ecMPA exhibits different absorption kinetics owing to the formulation; the tablets only dissolve under neutral pH conditions, and thus absorption only occurs in the intestine. It has a peak concentration after approximately 2 to 3 hours.
Cyclosporine lowers MPA concentrations by decreasing its enterohepatic recycling via OATP1B1 inhibition. Trough levels of MPA increase when cyclosporine administration is discontinued. This interaction is not seen with everolimus, sirolimus, or tacrolimus, and the maintenance dosage of MMF, when used with standard doses and blood levels of these drugs, is typically 500 to 750 mg twice daily. MMF should not be administered simultaneously with antacids, cholestyramine, sevelamer, or oral ferrous sulfate, all of which decrease intestinal absorption. MMF, as opposed to azathioprine, can be administered with allopurinol without dose adjustment. Potential interactions may occur when MMF is administered concomitantly with acyclovir and ganciclovir, and it is wise to discontinue MMF when there is evidence of systemic herpes infection necessitating use of high dosages of the antiviral drugs.
Reference
1- Up to date
2- Gabriel M. Danovitch, MD. Handbook of Kidney Transplantation. SIXTH EDITION.
Azathioprine
Dose, metabolism and Monitoring
-dose : 2.5mg/kg/day
-Collaborative Transplant study – patient who receiving steroids and Aza- doses greater than 1.5mg/kg/day were associated with greater graft function
-when administrated with CNI and steroid -1.5mg/kg/day (100mg/day) are appropriate
-Xanthine oxidase important in catabolism of mercaptopurine: allopurinol used with AZA need 25% Aza dose reduction – to avoid bone marrow suppression
Monitoring
-haematological parameters -leukocyte count <3
-thiopurine S-methyltransferase(TMPT) polymorphism associated with toxicity
Side effects
-bone marrow suppression- leukopenia, anaemia and thrombocytopenia
-megaloblastic anaemia due to hepatitis
-mercaptopurine metabolites intercalated into DNA of the skin increase sensitivity to UV light – risk for squamous cell ca but not basal cell ca
Mycophenolates
Dosing
-common dose – 1g BD
-IV same dose but infuse over 2 hours
Absorption
-orally delivered is rapid and almost completely absorbed
-hydrolysed to MPA
-absorption assessed by AUC- not significantly altered by food but Cmax is 40% lower in simultaneously fed renal Tx patient
-Tmax is less than 1 hour – independent of liver and renal function
-Tmax is delayed post Tx (1.31 SD 0.76 hours) and in DM patients
-MMf to MPA 94%bioavailability
-dose range of 100mg-3000mg is safe (MPA AUC for 24 H )
-EC-MPA – does not release MPA under acidic (pH<5) in the stomach but rapidly absorbed in intestine
-so T max is 1.5-2.75 h – delayed compared to MMF
-GI absorption is 93% and bioavailability of MPA after administration
-EC-MPS -720mg similar to 1000mg MMF
Metabolism and clearance
-rapidly metabolised to an inactive glucoronide (MPAG) via UGT1 in the GI, liver and some at kidney
-elimination – 17.9H ( healthy individuals)
-37%of patient shows secondary peak in plasma MPA concentration representing enterohepatic circulations
-MPAG binds to albumin (97%) but reversible
-estimate free MPA in ultrafiltrate samples did not show any benefit over total MPA level in predicting therapeutic vs adverse events
Blood monitoring
-measured in plasma by high performance liquid chromatography
-enzyme multiplier immunoassay technique (EMIT) -15-20% higher results because of antibody reagent cross reacts with acyl-MPAG metabolite
-EMIT -preferable and most widely utilised
-gold standard -sampling of blood over 12 hr period, with calculation of AUC conc-time exposure
-MPA AUC- calculated full ( 8 samples in 12H) or 2-5 samples over 4 hours.
-12H predose C0 MPA level are convenient
-MPA exposure increases by 30-50% after stable dose 1 week post RTx
-MPA exposure/dose relationship may differ in the settings of KTx, liver Tx, Small Bowel Tx, BM Tx
-due to differences in hepatic/renal function , concurrent drug administration, presence of diarrhoea-pharmacokinetic variability of MMF has been stated; not to gender and ethnicity
– peripheral blood lymphocyte from patients on MMf demonstrated reduced response to stimulation assay and diminished antibody production
-IMPDH assay -technically demanding and difficult to reproduce
-IMPDH activity level fluctuations made the assay difficult in predicting either the efficacy or toxicity of MMF in Tx
Therapeutic drug monitoring – MPA
-marked variabilities in pharmacokinetics provides a rationale to monitor
APOMYGRE
-all patients on CSA and steroids – randomised to receive fixed dose or CC MMF.
– measure the MMF level by limited sampling AUC and dose adjustment by Bayesian algorithm
-significant benefit in CC group with less rejection at 12 months
-MMF dose were higher in CC group with similar adverse events
FDCC study
-901 european KT recipients – randomised to CC (AUC 45mg/hr) or standard dose fixing
-two groups similar in rejections
-there is strong relationship between MPA exposure and rejection (37% had AUC 1.6 with reduced rejection rate
Recent consensus
-AUC target 30-60mg/hr/L
-recommended C0 >1.3mg/L with CSA and C0 >1.9mg/L with tacrolimus
FDCC and Opticept- 2g daily dose is adequate early MMF exposure in Tac combination
In standard patients, no clinical indication for therapeutic drug monitoring
May benefit in dual IS , patient under going CNI- or steroid sparing regimes, high immunologic risk, those with delayed graft function , or those with GI, hepatic or renal function
Drug interactions
-cholecystaramine -reduce MPA absorption
-antibiotics that disrupts GI flore –reduce UGT1 and enters hepatic circulation
-PPI- reduce MPA exposure by 25-35%
-CSA-reduce MPA conc due to reduce enters hepatic circulation
-co administration of Tac do not alter
-MPA with sirolimus – level of MPA higher
-steroids increases MPAG slightly by inducing hepatic glucuronosyl transferase
Cyclosporines
-CSA micemulsions (Neoral) had replaced the original oil based Sandimmune
Absorption and distribution
-bioavailability of microemulsions are better than oil based – less variability in CSA pharmacokinetics
-Cmax of Neoral is higher, and the trough Cmin correlates better with systemic exposure – reflected by AUC
-compared with IV bioavailability of the oral -30% to 45%
-conversion oral to IV form 3:1 dose ratio
-bioavailability of oral form increases with time due to P-gp group inhibitory properties of CSA
-reaches steady state at 4-8 weeks
-CSA -ME reaches max blood conc in 2H
-half life 6-27
-clearance 5-7mls/min/kg
-CYP3A4 primarily enzyme metabolise CSA
-bind predominantly with lipoprotein – toxic effect might exaggerated by low cholesterol and reduced by low cholesterol
ELITE-Symphony
->1600 subjects enrolled
-2 CSA -ME cohorts: normal and reduced dose CSA with MMF and daclizumab induction
-rejection rates after 1 year -25%
Tacrolimus (prograf)
-poor bioavailability
-but rarely require IV
-can be administrated in NG tube or sublingual
-IV dose – 1/3 of total daily dose by oral in 24 H continuous infusion
-sublingual dose usually have of the oral dose
-oral bioavailability -25%
-maximal blood level reached at 1-3 H
-gastric emptying of solids faster in those taking tac – beneficial to those gastric dysmotility disorders
-Diarrhoea increase the absorption of Tac
-Diurnal variation -Cmax morning -greater than those evening dose
Astagraf -Cmax after 2H
Envarsus XR – Cmax 6H
-high affinity for the formed blood elements
-not significant lipoprotein associated
-less unfavourable effect on the chol
-95% is bound to erythrocytes secondary to high conc of FKBP
-cross placenta barrier and enter breast milk
-breast feeding is not recommended
Metabolism and Excretion
-metabolised extensively by CYPP450 3A( 3A4,3A5)
-excreted in bile with minimal renal excretion
Therapeutic Drug Monitoring
-neoral – peak level ( after 2 H post dose)- so C2 may correlate better with drug exposure and clinical events
-tac – trough level is adequate to monitor
CsA
HPLC
– most specific method for measuring unmetabolised
-expensive and labour intensive
Immunoassay
-most common – Abbott ( Chicago IL) fluorescence polarised immunoassay (FPIA)
-has significant cross reactivity with CsA metabolite and over estimates CsA by 45%
Tacrolimus
-Abbott monoclonal antibody based – micro particle enzyme immunoassay (MEIA)- performed an automated instrument
-permits accurate estimation as low as 2ng/ml
-chemiluminescent microparticle immunoassay – detection limit up to 1ng/ml
-electrochemiluminescense immunoassay (ECLIA)- detection limit 0.5ng/ml
Corticosteroids
-Exert effect by blocking T cell derived and APC cytokine and cytokine receptor expression
-hydrophobic and can diffuse intracellularly
-inhibit translocation of factor KB
-inhibit IL-1,2,3,6,TNF-A
-metabolised by hepatic microsomes enzyme systems
Sirolimus
-mTOR inhibitors -key regulator in the process of cell division
-structurally related to tacrolimus
Mechanism of action
-bind to cytoplasm -binding protein
-TOR -regulatory protein in cellular proliferation G1 to S phase
Absorption and distribution
-rapidly absorbed from GIT
-reach high peak at 1-3 H
-oral dosing solutions has lower F than that with tablets
-92% protein bound
-largely metabolised by CYP3A and P glycoprotein
Therapeutic drug monitoring
-chromatography or immunoassay methodologies
-through level 5-15ng/ml depending on use of CsA
Bioavailability is the extent and the rate of active drug or it’s metabolites enter circulation; it’s depend on on properties of dose form.
Factors Affecting Bioavailability
* Absorption
* Food Effect
* Drug metabolism/ biotransformation.
* Energy dependent efflux transporters.
* Physico-chemical factors
* First pass metabolism
* CYP450 isozymes
Causes of low bioavailability:
– [ ] Oral dose with poor water soluble
– [ ] Insufficient time for absorption
– [ ] Chemical reaction that reduce absorption
– [ ] Age sex stress physical activity
Assessing bioavailability by determine area under a plasma concentration time, plasma drug concentration increase with extend of absorption.
The maximum plasma concentration is when drug elimination rate equal absorption rate.
The drug excreted unchanged in urine; the bioavailability can estimated by measuring the total amount of drug excreted after a single dose by 24 hr collection in urine.
Cyclosporine:
it’s oral dose
pretransplant dose 15mg /kg PO single dose
Post transplant dose 15mg /kg divided dose in first 2 weeks and then 5-10mg /kg divided dose.
Bioavailability of neoral > sandimmune.
Peak plasma time: neoral 1.5-2hr and sandimmune 3.5hr
90% protein binding
Volume distribution 13L/kg
Metabolism by CYP3A4
elimination 8.4 -27hr
clearance 5-7ml/kg
excreted by bile and faces. small amount by urine 6%.
Tacrolimus:
Oral dose
Inhibition T cell activation and proliferation and humoral immunity.
Bioavailability 7-32%
Peak time 0.5 to 6hr
99% protein binding
Volume distribution.05 to 4.7 l/kg
Metabolism in liver by CYP3A4
Excreted by faces
MMF
Inhibition T and B cell proliferation as well as antibody production.
Bioavailability 94% cellcept and 72% myfortic
metabolism by enterohepatic circulation
Peak plasma time 1.5 hr
Protein binding 82-97%
Volume distribution 3.6 L PO
Elimination half life 18hr
excreted metabolites in urine and faces.
Azathioprine:
it’s purine anti metabolites converted to 6 MP
Inhibition synthesis DNA RNA protein and interfere with cellular metabolism.
Well absorbed orally
peak plasma time PO 1-2 hr
protein binding 30%
metabolism by liver
excreted in urine primary as metabolites
References:
By Jennifer Le , Drug Bioavailability, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego
Last full review/revision Oct 2020
meant by bioavailability of a drugmeans the proportion of drug reach the periphreal blood and change into active form found that can be used by the body.
factors affect bioavaility of adrug
1-absoption
2-food effect
3-drug metabolism biotransformation
4-energy dependent efflux transporters
5-physico-chemical factors
6-first pass metabolism
7- CYP450 isozymes
Cyclosporin
bioavaililbility is variable range from 10% to 89% in various populationas result of lipophilliaty
absorption less depend on bile
volume of distribution range from 3 to 5L/kg
maximum concentration about 2 hour
at least 25 metabolites have been identified however theses metabolism are consider less than those of the parent companet
mainly excreated through GIT system.
Tacrolimus
The oral bioavailbility was poor and range from 11.2 to 19.1 in previous study
maxima concentration in the blood in 3 hour
volume of distribution is 0.68l/kg
mainly GIT excrection
MMF
absorp in small intestine
mean bioavailabiliy of of MPA from oral administeration of MMF estimate at 94.1% relate to i.v.
there is presystemic removal of MPA but enterohepatic circulation compensate for the first pass loss.
oral has 2 peak
first peak of conc one hour
second peak 8 to 12 hours
Azathioprine
6-mercaptopurine undergoes rapid and extensive catabolic oxidation to 6 thiouric acid in the intestinal mucosa and liver by enzyme xanthine oxidase
bioavaibility of 6- mercaptourine range from 5 to 37% in comparison , the intestinal absorption azathiopurine range from 50-72%
peak of conc in the plasma in 1 to 2 hour
volume of distribution is 1.7 l/kg
excerted mainly in the urine
References
1.MEHTA MU, VENKATARAMANAN R, BURCKART GJ, et al. Effect of bile on cyclosporine absorption in liver
2-Srinivas TR, Meier-Kriesche HU, Kaplan B. Pharmacokinetic principles of immunosuppressive drugs. Am J Transplant. 2005 Feb;5(2):207-17. doi: 10.1111/j.1600-6143.2005.00748.x. PMID: 15643980.
Bioavailability of a drug refers to the extent to which it drug reaches its destination and target after the initial dose.
In terms of our drugs, there may be minor differences between original and generics.
combinations also have affect. for example CsA vs TAC will affect the dose of MMF needed.
CsA reduces MMF exposure by 40% so we may need less dose on tacrolimus without risk of rejection compared to required dose when combined with CsA (In other words, to reach similar MPA exposure, the dose of MMF/EC-MPS will need to be higher if combined with cyclosporine)
https://www.sciencedirect.com/science/article/pii/S0085253821006864
3. What is meant by bioavailability of a drug? What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
Cyclosporine
Tacrolimus
MMF
Azathioprine
Bioavailability means the extent a substance or drug becomes completely available to its intended target(s).
Example: if 10 mg of a drug is given orally & 7 mg of this drug is absorbed unchanged, the bioavailability is 0.7 or 70%).
Bioavailability of a drug given by an IV route is by definition 100%.
For other routes it is 100% or less.
Bioavailability of oral medications depends on:
It physiological properties that affect its dissolution and absorption
Intestinal pH
Surface of absorption
Hepatic 1st-pass metabolism
Taking with food
Clinical implications of bioavailability:
When changing a formulation or a route of a drug, the dose needs to be adjusted accordingly.
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Cyclosporine
– Absorption is mainly in the intestine.
– Absorption is highly variable; peak bioavailability of 30% occurs 1-8 hours after oral dose.
– A 2nd peak seen in certain patients.
– Absorption from the GI is incomplete due to 1st– pass effects.
– Cmax in both the blood & plasma occurs at 3.5 hours post-dose.
– Absorption can be reduced by:
i) Timing & quality of food intake
ii) Interruption of enteric-hepatic circulation (especially after liver transplantation)
iii) Slow gastric emptying
iv) Diarrhea
v) Chronic and acute enteritis
vi) Intestinal autonomic neuropathy
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Tacrolimus
Tacrolimus activity is primarily due to the parent drug.
Absorption after oral administration is incomplete & variable.
Absolute bioavailablility is 17±10% in kidney transplant patients
Cmax occurs at 3.0 hours post-dose.
The rate & extent of tacrolimus absorption are greatest under fasting conditions.
Maximum absorption occurs when taken on an empty stomach.
Bile does not influence tacrolimus absorption.
Tacrolimus is metabolized primarily by cytochrome P-450 system (CYP3A).
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MMF
It is a prodrug of mycophenolic acid
Reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH).
Rapidly absorbed in the small intestine.
Cmax of its active metabolite, MPA, is at 60 to 90 minutes aftr an oral dose.
Bioavailability after oral dose is 94%.
Cmax of mycophenolate mofetil was 24.5 (±9.5)μg/mL.
====================================================================
Azathioprine
Azathioprine is a prodrug of 6-mercaptopurine.
It is metabolized by xanthine oxidase.
Xanthine oxidase inhibitors (allopurinol & febuxostat) may inhibit azathioprine metabolism, thus resulting in increased toxicity. Concurrent use of xanthine oxidase inhibitors & azathioprine should be avoided if possible. Otherwise azathioprine dose should be reduced.
Oral azathioprine is well absorbed, with a Tmax of 1-2h
Peak plasma concentrations are reached 1-2 hours after a dose.
Distributed rapidly throughout the body. The plasma half life is 3-5 hours.
========================================================================
References
1.MEHTA MU, VENKATARAMANAN R, BURCKART GJ, et al. Effect of bile on cyclosporine absorption in liver
transplant patients. Br J Clin Pharmacol 1988; 25: 579-584.
2.Drug Bank Online
3. MEDICATION GUIDELINES FOR SOLID ORGAN TRANSPLANTS,2021
Dear all
1.Please look at the table offered by Professor Ala Ali before answering it will save you a lot of time and effort.
2.Pregnancy and TX ,MMF is replaced by AZA and switched back some time after delivery ?
If you know why as I am sure you do
can you explain?
Which is the active metabolite
What is the situation in the Fortal. Lliver enzymes and what happens sometime after birth..
Foetal
☆ MMF and MPA are teratogenic in animal models, and an increasing body of evidence supports its teratogenicity in humans.
Patients with a desire to become pregnant should discontinue MMF at least 6 weeks before conception.
An increased rate of spontaneous abortion as well as congenital malformations with estimated rate of 25% has been reported, including a distinctive and unique phenotype associated with MMF exposure called the EMFO tetrad (ear, mouth, fingers, ocular/organ malformation).
The FDA has issued a black box warning based on the reports of teratogenicity, and contraception is mandatory for women with childbearing potential.
An early switch from MMF to azathioprine in women planning pregnancy is advised.
Uncertainty remains whether MMF/MPA should be stopped in men, but recent literature has indicated that paternal exposure to MPA is not associated with adverse birth outcomes.
After a switch, a longer observational period confirming stable kidney function or disease activity over time is of interest to reduce the complication rate during pregnancy.
☆ Exposure to azathioprine is reported to increase the risk of preterm and low-birth-weight infants, but no specific pattern or increased risk of malformations has been described. The former might be a direct consequence of the underlying disease rather than an effect of drug exposure.
☆ Both CNIs (cyclosporine A and tacrolimus) are relatively well tolerated during pregnancy: there are consistent reports of low birth weight for gestational age and premature birth but without increased risk of birth defects.
Trough levels may fluctuate during pregnancy due to an increase in enzymatic activity of the CYP3A family, altered volume of drug distribution, and changes in drug-binding components as albumin and hemoglobin levels decrease and the unbound fraction of CNIs increases.
To maintain a stable trough level, a CNI dose increase of approximately 20%-25% may be required during pregnancy. To date, there is no information about pregnancy outcome after voclosporin exposure, but animal data indicate a similar safety profile as observed for other CNIs.
—————–
Reference
Sam Kant, Andreas Kronbichler, Duvuru Geetha, Principles of Immunosuppression in the Management of Kidney Disease: Core Curriculum 2022,
American Journal of Kidney Diseases,2022, ISSN 0272-6386, https://doi.org/10.1053/j.ajkd.2021.12.011
The point of my question is:
The pregnant mother metabolites the AZA in. her liver to 6MP which is the active metabolite.
Then what happens to the feotus if he gets AZA FROM HIS MOTHER which will be toxic.
The feotus does not have the liver enzyme to do that BUT after birth he develops it and that is the mother has to stop AZA after delivery if she tends to breast feed.
The rest of your comments are correct.
Thank you Prof. Dawlat for your clarification
What is meant by bioavailability of a drug?
Bioavailability of a drug implies the proportion of the drug which reaches the peripheral circulation unchanged, in its active form, on introduction to the body. (1)
Bioavailability of an oral drug is calculated by comparing the AUC (area under the curve) or urine recovery of the unmetabolized drug after intravenous and oral administration. (2)
The oral bioavailability of a drug can be defined as:
Oral Bioavailability = (AUCoral/ AUCintravenous) x 100%
Bioavailability of an oral drug depends on:
1) Physicochemical barriers to absorption by the gastrointestinal mucosa
2) Gastrointestinal transit rate
3) First-pass/ pre-systemic metabolism and/or excretion by the gut and/or liver.
What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
References:
1) Broen JCA, van Laar JM. Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology. Nat Rev Rheumatol. 2020 Mar;16(3):167-178. doi: 10.1038/s41584-020-0374-8. Epub 2020 Feb 13. PMID: 32055040.
2) Srinivas TR, Meier-Kriesche HU, Kaplan B. Pharmacokinetic principles of immunosuppressive drugs. Am J Transplant. 2005 Feb;5(2):207-17. doi: 10.1111/j.1600-6143.2005.00748.x. PMID: 15643980.
Very good
Bio-availability
It is an important determinant of pharmacokinetic of a drug in which the fraction of total drug administered into the body reaches the systemic circulation in active form. It depends upon first pass metabolism and mode of entrance and blood flow. Bioavailabiloty is 100% in IV route whereas low in other routes
Transplant immunosuppressive drugs have following characters:-
1)Mycophenolate Mofetil :-
* 80% bioavailability
* meal decreases Cmax by 40% but AUC unchanged
* Hence should be taken in empty stomach
* half life -18 hours
2)Mycophenolate Sodium :-
*72% bioavailability
*meal decreases Cmax by 33% but AUC unchanged
* Hence should be taken in empty stomach
* Half life -12 hours
3)Cyclosporin:-
*Oral bioavailability 23-50%
*meal decreases Cmax by 33%
*meal also decreases AUC by 13%
*Ideally should be taken in empty stomach
*Half life 8 hours
*Prolonged in hepatic impairment
4)Tacrolimus:-
*Oral bioavailability 7-23%
*Fatty meal decreases Cmax by 77%
*Fatty meal decreases AUC by 37%
*Though carbohydrate also decreases Cmax and AUC but lesser than Fatty meal
*Half life -12 hour
*Ideally should be taken before meal
Tacrolimus extended release
*Oral bioavailability 12-19%
*Half life of 38 hours
5)Azathioprine:-
*Breakdown to 6-mercaptopurine
*Half life is 3 hours of active metabolite
*Can be taken with or without food
Good but missing:
Drug interactions
Doses
What is bioavailability
It refers to the exact level of drug that is made available in circulation for intended effects on target receptors after passing through different barriers . It can be affected by intrinsic or extrinsic factors like physical properties of drugs, dose, formulation and concomitant use of other medications ,foods etc. It can be 100 % for intravenous route while significantly lower in oral route. The time taken-Tmax to achieve maximum drug concentration and the actual maximum drug concentration will depend on multiple factors and will be different for each drug.
Cyclosporine
It can be given through IV and oral route and absorption can be affected by multiple factors including metabolism by CYP3A..Any substance which affects cytochrome can affect Cyclosporine bioavailability. Peak bioavailability can be achieved in 1-8 hours. About 50 % can be bound to blood elements like RBC and lymphocytes. It has narrow therapeutic range and close monitoring of drug levels is required. There can be significant drug interactions like phenytoin can reduce serum levels while erythromycin can increase the levels.
Tacrolimus.
It is metabolized by cytochrome CYp3A4/5 and can be given by both oral and intravenous routes. The oral formulation is availabe as 0.5, 01 and 5 mg. It has narrow therapeutic index and bioavailability can be between 5-93%. Oral dose is usually 3-4 times higher than IV dose. In the circulation it bind to proteins and RBCs. Peak level can be achieved in an hour. Metabolism can occur in intestine, liver and kidney. Bioavailability can be affected by multiple factors including diabetes, bowel resection , africo american or non white races.
Azathioprine.
It is an antimetabolite with narrow therapeutic range and bioavailability is around 50-70 percent and metabolized in the liver. After oral administration the absorption is quick and peak plasma levels can be seen in 1-2 hours. It is distributed in body fluids except extracellular fluids . Its use should be avoided along with allopurinol. Leukopenia can result if used with cotrimoxazole or ACE inhibitors. With the arrival of MMF its use has been discontinued mostly.
MMF
It blocks the proliferation of Band T cells by reversibly inhibiting inosine monophosphate dehydrogenase. Its is rapidly absorbed from gut and 90% is bound to plasma proteins. T max can be achieved in 1.5 hours. Absorption can be affected by antacids and cholestyramine. 93 % is eliminated in urine. Its available as 250 mg immediate release and 500 mg Tabs.
References
Handbook of nephrology and hypertension-Simon Steddon
Handbook of kidney transplantation – Gabriel M Danovitch
Drug interactions affecting bioavailability and doses!
-Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. The bioavailability of a drug is largely determined by the properties of the dosage form, which depend partly on its design and manufacture.
Cyclosporine:
-The original formulation of cyclosporine, the oil-based Sandimmune, has largely been replaced by the microemulsion formulation, Neoral.The bioavailability of the microemulsion formulation is better than that of Sandimmune, and there is less variability in cyclosporine pharmacokinetics.
-The improved gastrointestinal (GI) absorption of the microemulsion and lesser dependence on bile for absorption may reduce the necessity for intravenous cyclosporine administration.
-Compared with intravenous infusion, the bioavailability of the orally administered drug is in the range of 30% to 45%. Conversion between the oral and
intravenous forms of the drug perioperatively require a 3:1 dose ratio and is administered twice daily as 4-hour infusions.
– Bioavailability of oral cyclosporine increases with time.
-The amount of cyclosporine required to achieve a given blood level tends to fall with time and typically reaches a steady level within 4 to 8 weeks.
– Food tends to decrease the absorption of cyclosporine, although some foods can lead to increased absorption .
-The microemulsion formula of cyclosporine reaches maximal blood concentrations in approximately 2 hours.
-The volume of distribution is 3 to 5 L/kg, with the majority of the drug found in erythrocytes. It also exhibits very high protein binding in the plasma, especially to lipoproteins.
-The half-life varies from 6 to 27 hours with a clearance of 5 to 7 mL/min/kg.
-The drug is primarily eliminated in the bile with only 6% of the dose excreted in the urine, and with only 0.1% excreted unchanged.
-CYP3A4 is the primary enzyme system that metabolizes cyclosporine.
-In the blood, one-third of absorbed and infused cyclosporine is found in plasma, bound primarily to lipoproteins. Most of the remaining drug is bound to erythrocytes. Whole-blood drug levels are thus typically three-fold higher than plasma levels.
-The binding of cyclosporine to lipoproteins may be important in the transfer of the drug through plasma membranes, and the toxic effects of cyclosporine may be exaggerated by low cholesterol levels and reduced by high cholesterol levels.
Tacrolimus :
– it has relatively poor bioavailability, it is rarely necessary to use the intravenous
formulation. If necessary, the drug can be administered through a nasogastric tube or sublingually.
-Intravenous dosing is approximately one-third of the total daily dose required by the oral route and is administered via a 24-hour continuous infusion.
-Sublingual dosing is more variable, but is usually one-half that required by the oral route.
-With the immediate-release dosage forms, it is absorbed primarily from the small intestine, and its oral bioavailability is about 25%, with large interpatient and intrapatient variability, particularly for patients with GI disease.
-Maximal blood concentrations are reached in 1 to 3 hours.
-Diarrhea may lead to increased absorption of tacrolimus from the lower GI tract with resultant toxic levels.
-Immediate-release tacrolimus displays diurnal variation in its absorption profile. Cmax concentrations after morning dosing are typically greater than those found with the evening dose.
-The prolonged-release formulation, Astagraf XL, has a Cmax which occurs after approximately 2 hours, whereas that of Envarsus XR is approximately 6 hours.
– Food has a similar effect on absorption with both the immediate- and prolonged-release formulations as with cyclosporine; patients should be counseled to be consistent in how they take these medications concerning meals.
-Tacrolimus also has a high affinity for formed blood elements, but it differs from cyclosporine in that, although it is highly protein-bound, it is not significantly associated with lipoproteins, and it has a less unfavorable effect on the cholesterol level than does cyclosporine.
-Approximately 95% of the TAC is bound to erythrocytes secondary to the high concentration of FKBP found in these cells.
MMF :
– Orally administered MMF is hydrolyzed to MPA and is rapidly absorbed, producing a peak level in approximately 1 hour.
-The bioavailability of MMF is roughly 90%, with 97% of the MPA protein bound to albumin.
– Orally administered MPA exhibits different absorption kinetics owing to
the formulation; the tablets only dissolve under neutral pH conditions, and thus absorption only occurs in the intestine.
-It has a peak concentration after approximately 2 to 3 hours. For African-American patients, a higher dose may be required to produce the immunosuppressive benefit.
-The same doses when used early postoperatively can produce much higher concentrations several months later. Patients should be continuously monitored for adverse side effects and periodically be evaluated for an MPA dose reduction, if clinically appropriate.
– Azathioprine
-It is absorbed from the gut to about 88%. Bioavailability varies greatly between individual patients, between 30 and 90%, because the drug is partly inactivated in the liver.
References :
1.Jennifer Le. Drug Bioavailability .MSD MANUALProfessional Version.
2.Danovitch G.M handbook of kidney transplantation sixth edition.
Excellent review
Dosing?
What is meant by bioavailability of a drug?Bioavailability is the fraction of administered drug that reaches the systemic circulation.
Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form.
For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or seventy percent.
Implementation of bioavailability on planning the dose of the following immunosuppressive drugs
1-Cyclosporine non-modified (Sandimmune):its oral bioavailability generally poor and unpredictable:10 to 89% (renal transplant patients) Metabolized by CYP3A4 to reduced activity and inactive metabolites (eg, M1, M9, M4N) cleared fecally via bile so its half life increased with hepatic impairment.
–Cyclosporine modified (micro emulsion) (Neoral).
23 to 50% better absorbed than non-modified formulation in renal and liver transplant patients, respectively.
Both Should be taken at a consistent time each day in relation to meals.
Both affected by high-fat meal.
2-Tacrolimus immediate-release capsule (Prograf) its oral bioavailability 7 to 32%.Metabolized by CYP3A4/5 to active (eg, 13-O-demethyl) and inactive metabolites cleared fecally via bile so its half-life Prolonged in severe hepatic impairment.
High-fat meal: ↓C-max by 77% and ↓AUC by 37% Should be taken on an empty stomach.
Tacrolimus extended-release capsule (Astagraf XL) its bioavailability 12 to 19% and its half-life is (35 to 41 hrs.) which used mainly with patient with peak dose toxicity as headache or tremors.
Tacrolimus extended-release tablet (Envarsus XR) its bioavailability 50% better absorbed than immediate-release capsule.
3-Mycophenolate mofetil (MMF, CellCept)/ Mycophenolate sodium, enteric coated (Myfortic) their bioavailability 80.7% and 72% respectively.
With tacrolimus decrease dose of MMF but increase with cyclosporine as it interrupt enterohepatic circulation.
Should be taken on an empty stomach or at a consistent time each day in relation to meals to improve GI tolerability.
Giving total daily dose in three or four equally divided doses may improve GI tolerability.
4-Aazathioprine:
Has poor oral bioavailability ( nearly 50 % of oral dose absorbed and so equivalent IV dose is half oral one ).
Half-life of parent drug is 12 min but for active metabolite 6-MP is 0.7-3 hours. Slightly prolonged in end-stage renal disease.
References:
1-Up to date.
2- Tsipotis E. Gupta N.R, et al (Bioavailability, Efficacy and Safety of Generic Immunosuppressive Drugs for Kidney Transplantation: A Systematic Review and Meta-Analysis), American Journal of Nephrology, 2016, Vol.44, No. 3.
Good but you all missed the purpose of the question which is the effect on dosing.
Drug interactions?!
Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. Bioavailability of a drug is largely determined by the properties of the dosage form, which depend partly on its design and manufacture.
For intravenous route bioavailability is 100%, while in other routes of administration such as oral route it could be lower due to first pass effect.
Drug bioavailability after oral administration is affected by a number of different factors, including physicochemical properties of the drug, physiological aspects, the type of dosage form, food intake, biorhythms, and intra- and interindividual variability of the human population. Accordingly immunosuppressant agent should be monitored by assessing their blood level.
Cyclosporine:
Tacrolimus:
MMF:
Azathioprine:
References:
Well done
Bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered.
The route of administration and the dose of a drug have a significant impact on both the rate and extent of bioavailability. The dose of a drug is indirectly proportional to its bioavailability.
Cyclosporine
In plasma, it is 90% protein bound, mostly to lipoproteins.
In blood, cyclosporine is extensively distributed in erythrocytes. There is significant interindividual variability in intestinal absorption, furtherly influenced by food , diabetes, gastric motility problems, and diarrhea .
It’s variability in intestinal absorption has been solved by the creation of the microemulsion formulations.
CsA is metabolised by the cytochrome P450 system, primarily CYP3A4, and CYP3A5 . Coadministration of medications known to inhibit the cytochrome P-450 system increase cyclosporine levels ,while inducers of the P-450 system decrease it’s levels .
CsA nephrotoxicity is dose dependent and reversible upon dose reductions or discontinuation of the drug.
It was noticed that using a dose of 25 mg/kg had a significant unexpected nephrotoxicity.
Follow-up studies using a lower dose (17 mg/kg) showed improved outcomes with this strategy with a one-year predicted graft survival rate of 86%.
Other studies have also demonstrated improved GFR and blood pressure measurements using a target of fifty percent of the standard area-under-the-curve (AUC) dose
Meanwhile the desire to reduce CsA exposure without risking under immunosuppression led to protocols including other immunosuppressive agents as using of antilymphocytic antibodies in the early posttransplant period in an attempt to avoid early CsA exposure until such time that allograft function was fully recovered.(1)
Tacrolimus
It has narrow therapeutic index (between 5 and 15 ng ml) and wide intra- and interpatient variability.
The oral bioavailability of tacrolimus is poor could be due to gut metabolism or to poor oral absorption of the drug, because of this it is administered intravenously during the immediate postoperative period.
There is a significant correlation between increased Tac .trough concentration and decreased risk of acute rejection, but there is a poor correlation between it’s dose and trough concentrations.
when prednisone dosage was >25 mg, Tac clearance was increased, it could be due to corticosteroid induction of CYP3A.(2)
The immediate-release formulation of tacrolimus was administred twice daily (IR-Tac and generics, Prograf) and in order to improve treatment adherence, tacrolimus was formulated as a prolonged-release once-daily formulation (PR-Tac, Advagraf) which improved adherence, having also non-inferior efficacy and similar tolerability compared to IR-Tac.
A novel once-daily formulation of tacrolimus was developed based on the MeltDose drug delivery technology (LCPT, Envarsus) enhancing the bioavailability of low water solubility drugs by decreasing its particle size, thereby controlling its release and allowing a more distal distribution of the drug within the gut, with a 30% reduction of total daily dose (TDD) and a lower peak and less peak-to-trough fluctuation.
Studies reported the higher bioavailability of LCPT versus PR-Tac and a lower incidence of BK infections .(3)
MMF
MMF is an ester prodrug of mycophenolic acid (MPA) and MPA has a narrow therapeutic window and large inter-individual variability, therfore therapeutic drug monitoring (TDM) of the area under the concentration–time curve for the 12-h of exposure (AUC0-12 h) of MPA (MPA-AUC0-12 h) is essential to improve clinical outcomes.
The two formulations of MMF ;dispersible tablet and capsule were bioequivalent
When giving 750 mg twice daily, most patients can reach the target exposure in 1st week after renal transplantation.
An appropriate AUC0-12 h after drug administration, between 30–60 μg⋅h/mL, was associated with significant decrease in acute graft rejection
TDM of MPA is significant in performing personalized prescription for the prognosis of recipients.
The C0 level was not a reliable parameter to assess the MPA exposure .
The 4-point method (C8, C2, C4, and C1) was the best Limited sampling strategy (LSS), it was recommended for predicting MPA-AUC0-12 h in early renal transplant recipients
The concomitant use of cyclosporine lowered MMF level more than concomitant Tac administration.(4)
Azathioprine
It is well absorbed following oral administration. The absolute oral bioavailability is estimated to be between 41% and 47%. Protein binding of azathioprine is approximately 30% and it is partially dialyzable. Metabolites of azathioprine are primarily excreted via the kidney, with very small amounts of the parent compound excreted intact. The t1/2 of azathioprine is approximately 3 hours.(5)
Studies demonstrated that, in tacrolimus-based immunosuppression, azathioprine may be as good as MMF as maintenance immunosuppressive drug in living donor kidney transplantation particularly it is a more cost-effective immunosuppression.(6)
Reference
1-Tedesco D.etal .Cyclosporine A Review Journal of Transplantation 2012 , Article ID 230386, 7 pages
2- M. Antignac et al. Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients. Br J Clin Pharmacol 64:6 750–757
3-FernandezRiveraetal.Bioavailability of once daily tacrolimus formulations used in clinical practice in the management of DeNovo kidney transplant recipients :the better study. Clinical Transplantation.2022;36:e14550.
4- Zhang J. et al. Pharmacokinetics of Mycophenolate Mofetil and Development of Limited Sampling Strategy in Early Kidney Transplant Recipients.Frontiers in Pharmacology 2018;9;908.
5- Chaballa M etal .Transplant Medicine. Pharmacology and Therapeutics .Principles to Practice 2009, 1269-1294.
6- Bansal S .B .etal. Comparison of azathioprine with mycophenolate mofetil in a living donor kidney transplant programme. Indian J Nephrol. 2011 Oct-Dec; 21(4): 258–263.
Well done though you give the impression that TAC is routinely given Iv early post transplant..?
bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered.
It is affected by many factors the most important is the mode of administration , first pass effect, other medications, protein binding , ingested food, dose , concentration and the volume of distribution.
Cyclosporine is a lipophilic polypeptide. The enteric oral absorption of cyclosporine is a process dependent on bile salt secretion. Furthermore, many physiological and pathological conditions, such as timing and quality of food intake, interruption of enteric-hepatic circulation , slow gastric emptying, diarrhea, chronic and acute enteritis, intestinal autonomic neuropathy and alterations of gastroenteric functionality among others, can significantly reduce cyclosporine absorption. These conditions can cause a considerable inter- and intra-patients variability in gastrointestinal absorption. Also cyclosporine bioavailability after oral administration varies between 20 and 60% of the given dose and increases with time after kidney transplantation
Regarding tacrolimus
The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1% in adult kidney recipients.
The low bioavailability of tacrolimus could be due to gut metabolism or to poor oral absorption of the drug. Incomplete absorption of tacrolimus is largely responsible for the low bioavailability of the drug .
Some factors, such as changes in gastrointestinal motility after surgery, could explain the low clearance immediately after surgery and recovery after a few days. After a long duration of surgery, as in transplantation, some disorders have been observed and the time to obtain the maximal value for clearance could correspond to the recovery of metabolic function
A significant relation is found between tacrolimus clearance and oral corticosteroid dosage during months 2–12 post transplantation in kidney transplant recipients, indicating that corticosteroids increased the metabolism of tacrolimus. This could have resulted from corticosteroid induction of CYP3A.
Tacrolimus, however, is poorly bioavailable in patients awaiting renal transplantation (mean bioavailability of 14%, range 6–36%)
MMF
a prodrug of mycophenolic acid (MPA), after oral and intravenous administration. The plasma MPA profile of oral MMF showed a sharp peak at approximately 1 hour and a secondary peak at 8 to 12 hours. Mean apparent plasma t1/2 of MPA was similar for both routes (approximately 17 hours).
The mean bioavailability of MPA from oral administration of MMF estimated as 94.1% relative to the intravenous route.
Azathioprine is well absorbed following oral administration. The absolute oral bioavailability is estimated to be between 41% and 47%. Protein binding of azathioprine is approximately 30% and it is partially dialyzable. Azathioprine undergoes metabolism to 6-MP in the liver . 6-MP undergoes further metabolism via oxidation and methylation in the liver and in erythrocytes. Metabolites of azathioprine are primarily excreted via the kidney. The t1/2 of azathioprine is approximately 3 hours.
Check this and comment
Comment on this graph according to the above-mentioned Medications.
MMF has 2 peaks of concentration in the blood : the 1st peak after 1.5 hours, the 2nd peak after 6-12 hours because of the enterohepatic circulation, therefore the bioavailability of MMF is higher than azathioprine and tacrolimus.
Excellent
_ simply, drug bioavailability means the proportion or the drug that reaches the systemic circulation to be available at the target site of action, which is affected by many factors in case of Oral drugs as immunosupressives used in the field of transplantation.
_ the drug bioavailability can be detected be comparing the plasma concentration of the drug after oral and IV route of administration.
_ factors affecting it are the drug dose, formulation, solubility , absorption, metabolism and 1st pass metabolism in liver or intestine which have marked intra and inter individual variability.
_ as regard CNI:
a. For both ciclosporin and tacrolimus
b. It’s metabolized by cytochrome P450 ( it’s subtypes CYT P 3A4 and 3A 5 which are affected by many factors:
_ drugs as enzyme inducers like phenytoin and rifampin which can increase drug elimination and predispose to rejection, or enzyme inhibitors as antifungal )ketoconazole or antibiotics like erythromycin) which increase trough level and predispose to CNI induced toxicity as nephrotoxicity with ciclosporin and neurotoxicity with tacrolimus. _ the concept of increased Tacrolimus trough level by ketoconazole has been utilized to decrease required dose and financial burden.
I think also phenobarb can be used to manage drug intoxication.
_ pharmacogenetics also play a role , as individual variation in Cyt 3A4 and multidrug resistant gene (MDR1) which encodes for glycoprotein P-gp which is intestinal and hepatic efflux protein for such drugs makes some people slow metabolizers of the drug and liable to toxicity and others rapid metabolizers and liable to rejection.
_ in addition, lipophilic nature of ciclosporin makes it high volume of distribution and render it’s efficacy in some patients with excess fat tissue and hyperlipidemia ( only small proportion of the drug available at site of action).
_ other drug drug interaction as statin which are also metabolized by CYt p enzyme, so concomitant use may increase competition on enzyme binding site and enhance toxicity of either of them ( rhabdomyolysis from increased statin or nephrotoxicity from CNI).
As regard tacrolimus:
_ the same as ciclosporin , but less oral bioavailability in addition has rapid emptying time so increase risk of toxicity in patients who have diarrhea
_ As regard MMF: either prodrug mycophenolate mofetil or active mycophenolic acid (MPA, myfortic) , enteric coated
With less GIT side effects with mycophenolate mofetil.
_ MMF is extremely affected and poorly absorbed by fatty meals , so should be taken on empty stomach
_ as regard azathioprine ( anti proliferative): its use has declined and replaced by the more potent MMF.
_ poor oral bioavailability ( nearly only 50 % of oral dose absorbed and so equivalent IV dose is half oral one ).
– serious BM depression occurs when used together with allopurinol so better reduction of dose to half or avoided .
_ use of cholestyramine chelates of these drugs especially MMF , so better taken away from time of medications
Use of Lipid apharesis in case of multidrug resistant nephrotic syndrome to control dyslipidemia and enhance response to steroid and CNI , explains how pharmacokinetics greatly influence response to drugs and emphasize importance of control of hyperlipidemia to achieve adequate response to CNI
Good knowledge but you missed half of your answer which is how can bioavailability affect the dosing issue.
I will revise that dear professor
Implementation of drug bioavailability on planning the dose:
o It is a prodrug with oral bioavailability: 94%. Max blood concentration in 1 ½ hours, second peak 6-12 hours later due to enterohepatic circulation. Volume of distribution: 0.71 L/kg. Primarily eliminated in urine (93%).
o Enteric coated MMF absorbed only in small intestine, with peak concentration after 2-3 hours. AUC of mycophenolic acid increases over time.
o The bioavailability of the drug gets reduced with fatty diet, hence better to take empty stomach to increase absorption.
Drug interactions
What is meant by bioavailability of a drug? What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
bioavailability is stated to as the level and degree to which the active drug element or active fraction of the product is absorbed and becomes available at the site of drug action.
Measured by Using the area under the blood or plasma concentrate time cure (AUC), or maximum concentration max (con.)
Bioequivalent mean if we have two formulation of the same drug or two drug products like generic product but is assume that they will provide same therapeutic effect and can be used interchangeably means they contain same active ingredient but not necessarily in the same dosage form or same salt or ester in other word they are pharmaceutical equivalents.
Generic drugs mean they are identical to the brand name, FDA approved their use o in order to make it available with less cost, safe with similar efficacy to original brands after validation by bioequivalence clinical trials taken in consideration the drug absorption profiles, therapeutic efficacy, and safety.
Cyclosporine:
Selective inhibition of calcineurin by impair the IL2 transcription inhibition T cells its lipophilic molecules with large volume of distribution, dose not cross the BBB, available as modified and non-modified formula, oral formulation is partially absorbed with large inter-an intra individual variation, oral bioavailability is limited due to poor absorption, partial metabolism by the intestinal enzymes, first-pass, hepatic metabolism via cytochrome 450,cyp3A , P-gp efflux which can be affected by enzymes inducers or inhibitors drugs with the risk of under suppression or CNI toxicity respectively , excreted into the bile and liver dysfunction can prolongs the Half-life
Tacrolimus:
Similar to cyclosporine, tacrolimus ( prograf ),oral and IV
Immediate release capsules can be used every 12 hours, low oral bioavailability around 25%, absorption by small intestine with large inter and intra patient variability, maximum blood concentration reached in 1-3 hours with rapid gastric emptying compared to cyclosporine, that’s why the risk of tacrolimus toxicity is more in patient with diarrhea and motility disorders due to increased absorption of the tacrolimus from lower gut and increase drug level
Immediate release formula has diurnal variation in its absorption profile, Cmax aftr morning dose more than evening dose.
While XR formulation, has Cmax after two hours, and envarsus xr after 6 hours
oral suspension formula available.
Many generic brands with conversion ratio of 15% from the original brand, close monitoring with trough level
Long-acting formula available like astagrafXL , envarsus XR , FDA a approved ,used once /day
GI absorption is independent of bile salt, poor bioavailability, IV formula also available with dose conversion one third of total oral dose by 24 h infusion, can also give through NGT and sublingual variable dosing but usually use one – half the total oral dose
MMF:
Active drug related to mycophenolic acid and mofetil moiety serves as important part that enhance the oral bioavailability, MPA is very selective antimetabolite, with selective effect on lymphocytes and blocks the proliferation of T and B cells, inhibits Abs production and inhibits the generation of cytotoxic T cells also downregulation of the adhesion molecules on lymphocytes so its effective in treatment of ongoing rejection and prevent the progression
Both MMF ( cellcept) is the morpholinoethyle ester of MPA, available in the immediate release 250mg capsules and 500mg tablets , also there is suspension formula
The enteric coated MPA ( myofortic ), delayed release formulation of MPA both available as generic form as well
MMF rapidly absorbed after oral administration, produce peak level after 1 hour with 90% bioavailability high protein bound 97%, absorption affected by the PH and need neutral PH. Peak concentration reached after 2-3 hours, in black African American patients need higher dosesAUC of MPA increases overtime and need close monitoring for the side effects and careful dose adjustment.
Safety concern including GI side effects most common diarrhea around 1/3 of cases, dose related
CMV infection, Bone marrow suppression Therapeutic drug monitoring not done in routine practice but in case of side effects sending the AUC for MPA may require for dose adjustment
Only Cyclosporine lowers MPA concentration by decreasing the enterohepatic recycling via OATPIBI inhibition and MPA trough level increase when cyclosporine discontinued
Some drugs interfere with the intestinal absorption of MMF and should avoid given such drug at same time with MMF like antacids , oral iron supplements , sevelamer
Azathioprine:
Purine analogue its antimetabolite that act on inhibition of purine synthesize and interfere with synthesis and metabolism of ribonucleic acid RNA so it inhibits gene replication, cheap immunosuppression has been in use for more than 50s earlier with steroid then with cyclosporine combination, in the era of MMF nowadays its use individualized for specific conditions, it’s a potent myelosuppressive therapy that suppress the promyelocytes in the bone marrow and further inhibit the differentiation of the myelocytes to macrophage in primary immune response.
half of the oral dose will be absorbed and IV dose equivalent to the half oral dose
main side effects, hematological myelosuppression, need regular monitoring with FBC, wbc count and platelet count
also, can cause hepatitis and pancreatitis in less extent, combination with allopurinol should be avoided or used with caution and reduction of the dose by 25-50% with close monitoring with FBC.
References:
1-Chow SC. Bioavailability and Bioequivalence in Drug Development. Wiley Interdiscip Rev Comput Stat. 2014;6(4):304-312.
2-Kidney transplant hand book 6th edition.
1- Up to date medicine .
Excellent
☆ Bioavailability is the extent a substance or drug becomes completely available to its intended biological destination. It’s a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
° Bioavailability is an integral part of the pharmacokinetics paradigm. Pharmacokinetics is the study of drug movement through the body and is often represented by the acronym ABCD which stands for administration, bioavailability, clearance, and distribution.
° The bioavailability of a drug may be affected by intrinsic or extrinsic variables.
Intrinsically, a drug’s bioavailability can be affected by the drug’s required metabolic steps to activation, the specificity of its target receptors, the patient’s unique physiology (including phenotypic polymorphisms), route of administration of the drug, and site of drug absorption.
Extrinsic variables affecting drug bioavailability include interactions with concurrent food or substance metabolic processes and drug interactions with medications.
° The bioavailability (F) of a drug delivered via other routes of administration can be determined by the mass of the drug delivered to the plasma divided by the total mass of the drug administered (Equation 1):
Equation 1: F = mass of the drug delivered to the plasma ÷ total mass of the drug administered
Bioavailability can be derived from an area under the curve (AUC) graph (Equation 2).
Equation 2: F = AUC for X route of administration ÷ AUC for IV administration
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☆ The oral bioavailability of MMF is 94%, with half-life of approximately 17.9 ± 6.5 hours.
The metabolism of MMF is hepatic, where it is hydrolyzed to MPA and a component of enterohepatic circulation.
Dose reduction should be considered in severely decreased kidney function given the MMF AUC is increased 75% with estimated glomerular filtration rate (eGFR) <25-30 mL/min/1.73 m2, with no adjustment recommended in the setting of severe hepatic parenchymal disease.
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☆ The bioavailability of azathioprine is 16%-50%, with predominant hepatic metabolism. The elimination half-life is about 2 hours, with excretion primarily in the urine.
Dose reduction is usually recommended in the setting of oliguria/acute tubular injury. Genetic polymorphisms of certain enzymes play an important role in the metabolism of azathioprine, namely thiopurine S-methyltransferase (TPMT) and nucleoside triphosphate diphosphatase (NUD15).
Deficiency of TPMT can cause accumulation of 6-thioguanine nucleotides and 6-methylmercaptopurine, leading to hematological toxicity and hepatotoxicity.
Xanthine oxidase inhibitors (allopurinol and febuxostat) should be avoided during azathioprine use, given the risk of accumulation of 6-mercaptopurine by slowing elimination, with consequent serious toxicity.
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☆ The bioavailability of tacrolimus is variable (17% ± 10%), with a half-life of 23-46 hours; the bioavailability of cyclosporine is 30%-68%, with half-life of 5-18 hours.
The suboptimal bioavailability of both drugs is attributed to poor intestinal absorption, partial enzymatic metabolism in gastrointestinal mucosa, and first-pass hepatic metabolism.
Both CNIs are metabolized by the CYP3A system and are excreted via the biliary route (liver dysfunction prolongs the half-life of both drugs).
It is recommended that tacrolimus immediate release and cyclosporine be monitored with 12-hour trough levels.
Dose changes are usually reflected in 2-3 days for both CNIs. For tacrolimus, dose adjustments of 0.5-1.0 mg per dose should occur depending on trough levels; the range for change for cyclosporine is 25-50 mg.
It is imperative to verify whether the trough levels guiding these changes are accurate in relation to timing of administration.
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Reference
(1) Sam Kant, Andreas Kronbichler, Duvuru Geetha, Principles of Immunosuppression in the Management of Kidney Disease: Core Curriculum 2022,
American Journal of Kidney Diseases,2022, ISSN 0272-6386, https://doi.org/10.1053/j.ajkd.2021.12.011
(2) Price G, Patel DA. Drug Bioavailability. [Updated 2021 Sep 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.
(3) Tsipotis E, Gupta N, R, Raman G, Zintzaras E, Jaber B, L: Bioavailability, Efficacy and Safety of Generic Immunosuppressive Drugs for Kidney Transplantation: A Systematic Review and Meta-Analysis. Am J Nephrol 2016;44:206-218. doi: 10.1159/000449020
Excellent
Assignment III
What is meant by bioavailability of a drug?
Bioavailability is an integral part of the pharmacokinetics paradigm. Bioavailability refers to the extent a substance or drug becomes completely available to its intended biological destination(s). More accurately, bioavailability is a measure of the rate and fraction of the initial dose of a drug that successfully reaches either; the site of action or the bodily fluid domain from which the drug’s intended targets have unimpeded access.
What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
Cyclosporine
The original formulation of cyclosporine, the oil-based Sandimmune, has largely been replaced by the microemulsion formulation, Neoral. Both formulations are available in two forms: a 100-mg/mL solution that is drawn up by the patient into a graduated syringe and dispensed into orange juice or milk, and 25-mg and 100- mg soft-gelatin capsules.
The bioavailability (F) of the microemulsion formulation is better than that of Sandimmune, and there is less variability in cyclosporine pharmacokinetics. the bioavailability of the orally administered drug is in the range of 30% to 45%.
In the blood, one-third of absorbed and infused cyclosporine is found in plasma, bound primarily to lipoproteins.
Tacrolimus
Tacrolimus (Prograf ) is available in an intravenous formulation, and as 5-mg, 1-mg, and 0.5-mg immediate-release capsules.
A suspension formula can be compounded, but is not commercially available. GI absorption is independent of bile salts. Despite its relatively poor bioavailability, it is rarely necessary to use the intravenous formulation. If necessary, the drug can be administered through a nasogastric tube or sublingually. Intravenous dosing is approximately one-third of the total daily dose required by the oral route and is administered via a 24-hour continuous infusion.
Both cyclosporine and tacrolimus are metabolized extensively by the cytochrome P450 (CYP) 3A enzymes, specifically 3A4 and 3A5. This primarily occurs in the small intestine, liver, and to a certain extent in the kidney. Both agents and their metabolites are also substrates for P-glycoprotein (P-gp) efflux pumps.
MMF
CellCept is the morpholinoethyl ester of MPA and is available for clinical use in immediate release 250-mg capsules and 500-mg tablets. A suspension formulation is also commercially available. The standard dose is 1 g twice daily. An intravenous preparation is available but is usually not required in kidney transplant recipients. Myfortic (ecMPA) is a delayed-release formulation of MPA as a sodium salt and is available in 180-mg and 360-mg tablets: the standard dose when used is 720 mg twice daily.
The pharmacokinetics of MPA is complex. Orally administered MMF is hydrolyzed to MPA presystemically and is rapidly absorbed, producing a peak level in approximately 1 hour. The bioavailability of MMF is roughly 90%, with 97% of the MPA protein bound to albumin.
MPA is glucuronidated via glucuronyl transferase enzymes in the liver to a pharmacologically inactive form (MPAG). Enterohepatic cycling of MPAG can occur via OATP transportation of MPAG from the liver into the bile.
Neither MMF nor MPA is dialyzed.
Azathioprine
Azathioprine (Imuran) is an antimetabolite, an imidazole derivative of 6-mercaptopurine.
When cyclosporine was introduced, the role of azathioprine was largely relegated to that of an adjunctive agent, and with the introduction of MMF, its use has been discontinued in many programs.
The absorption of orally administered AZA is rapid. Peak plasma concentrations of 6MP, an intermediate metabolite of AZA, has been observed within 1-2 hour.
studies demonstrated that AZA is rapidly converted into 6MP. doses are still based on body weight. Typically, patients undergoing renal transplantation do not receive more than 3 mg/kg orally except in the first few days after transplantation.
Cyclosporine is found in plasma and RBCs otherwise well done
Bioavailability: is a fraction of drug that reach systemic circulation or it is a degree or rate of substance ( e.g. dug) that absorbed into circulation or made available at site of physiological activity. There are several factors affect bioavailability:
Cyclosporine:
Can be given orally or through IV route. It has variable oral absorption & inter- & intra-individual variability ( e.g. some patient receive same dose may had acute rejection while other develop toxicity with same dose), & this may be due to its metabolism by CYP3A4 in GIT ( had many interaction with substances can induce or suppress this cytochrome).
50% of the drug bound to blood fraction( 1/2 bind to RBC & <1/10 bind to lymphocytes). So it has narrow therapeutic range & many substances interaction & need close monitoring of drug level.
Tacrolimus:
Can be given orally or IV infusion, but oral absorption incomplete & variable, so need dose tailoring. It metabolized through CYp3A4/5 ( similar to cyclosporine, & drug that can affect metabolism of this cytochrome can affect drug level of tacrolimus). Bioavailability range from 5-93%( narrow therapeutic range), in general oral dose should be 3-4 times higher than IV dose.It highly bound to serum protein & RBC (99%). It absorbed rapidly with peak concentration 0.5-1 hour.
Bioavailability can be reduced in:
Azathioprine:
Metabolized in liver to 6-mercaptopurine then to thioinosinic acid. Bioavailability 50-72%, & 30% of drug is bound to albumin, once enter the circulation distributed widely throughout the body except CSF. Had long duration of action with narrow therapeutic range.
Using with ACEI or cotrimoxazole can enhance leukopenia, also it should be avoid AZA use with allopurinol ( if used together the dose of AZA should be reduced by 60-75%.
MMF:
potent reversible inhibitor of inosine monophosphate dehydrogenase, so it rapidly block proliferation of both T & B cells. Highly bound to plasma protein( >90%). Rapidly & completely absorbed after oral administration. Several drugs can reduce its absorption e.g. antacid containing Mg & AL, & cholestyramine.
References:
Fine you missed some doses.
How canTAC bioavailability be affected by long waiting time?
What exactly is meant by the term “bioavailability of a drug”?
bioavailability is defined as the proportion of the active form that enters the systemic circulation unmodified.
Tacrolimus:
Cytochrome P450 3A4 (CYP3A4) is the major isoenzyme responsible for the metabolism of tacrolimus and other anti-inflammatory drugs.
Extrahepatic metabolism by CYP3A4 in the gastrointestinal epithelium is responsible for approximately half of the absorbed dosage being eliminated before it reaches the liver.
CYP3A4 in the liver is responsible for an extra 10% of total elimination, resulting from first-pass metabolism.
tacrolimus immediate-release capsule (Prograf)bioavailability varies from 7 to 32 per cent when taken orally.
Cyclosporin:
Cyclosporin’s bioavailability varies from person to person. The percentages ranged from 10 per cent to 89 per cent. The peak bioavailability occurs 1-8 hours after the intake of the medication.
There are clinically significant pharmacological interactions between CsA and a variety of different medicines. Some drugs, such as phenytoin, can lower trough blood CsA concentration to subtherapeutic levels, whilst other drugs, such as erythromycin, can elevate CsA concentrations to potentially dangerous levels.
MMF:
There are two forms of mycophenolic acid (MPA) on the market: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). MMF is a prodrug that was created in order to increase the bioavailability of MPA in patients. By delaying the release of MPA into the small intestine rather than the stomach, EC-MPS has the potential to lower the occurrence of unfavourable gastrointestinal (GI) symptoms, primarily diarrhoea.
The bioavailability of both formulations is roughly 90%, but when taken with a high-fat meal, the bioavailability is dramatically lowered to approximately 80%. Because of this, both formulations should be consumed on an empty stomach in order to maximize absorption.
Azathioprine: is a medication that is well absorbed after being taken orally. The peak in serum radioactivity occurs 1 to 2 hours following oral administration of the radioisotope. The fact that only a part of the radioactivity is present as azathioprine is a result of extensive metabolism.
REFERENCES
-Up-to-date
What is meant by bioavailability of a drug?
The extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action.
implementation of bioavailability on planning the dose of:
Absorption: only partially absorbed in the small intestine with large inter and intra-individual variability, peak concentration occurs after 1-8 hours.
Oral bioavailability is limited as a result of poor absorption, partial metabolism by enzymes in the gut, and first-pass hepatic metabolism. modified formulations lead to higher AUC.
The absorption and metabolism may vary with race and ethnicity with a lower rate among African-Americans.
Absorption is also dependent on bile salts, thus modified formulations are prefered in patients with biliary diversion or cholestasis.
Patients who are using cyclosporine ophthalmic emulsion have no significant systemic absorption.
Metabolism in the liver through cytochrome P-450, some metabolism occurs in the gut mucosa.
The cyclosporine metabolites have only 10-20% of the drug IS activity.
Interaction with food( grapefruit) and drugs.
Absorbed in the small intestine, oral bioavailability is limited ( 20%).
The oral bioavailability of extended-release tac is 50% higher as compared to the immediate-release formulation.
Extended-release tac formulations exhibit chronopharmacokinetic effects, evening administration compared with morning dosing results in 15% lower AUC for extended-release tac tablets and 35% lower AUC for extended-release tac capsules, thus both should be taken consistently every morning.
Extended-release tac capsules have AUC0-24 higher than that of immediate-release tac.
Tac absorption is lower in the African-American population may be due to the differences in the frequency of polymorphisms in the CYP3A5 gene.
Tac is minimally absorbed in patients with normal skin but significant absorption has been reported in patients with skin disease.
Metabolised extensively by cytochrome P-450 in the liver.
The metabolite of Tac possesses the same efficacy as the parent drug.
Interact with food ( grapefruit) and drugs.
Drugs that increase the concentration :
diltiazem, ketoconazole, erythromycin
Drugs that may lower tac concentration:
anticonvulsant and anti-TB
Bioavailability is 90% and significantly reduced when taken with a high-fat meal so it should be taken on an empty stomach and to improve GI tolerability, it may be taken with meals at consistent times each day.
Dose adjustment is required in severe chronic renal failure due to the prolongation of the half-life of MPAG.
Metabolised by cytochrome 3A4/5
Drug interaction:
Drugs that decrease MMF absorption:
antacids, mineral supplements, sevelamer, bile acid sequestrants, PPI, rifampicin
Drugs that increase MMF level;
acyclovir, valacyclovir, probenecid
Absorbed from the gut. bioavailability varies greatly between individuals ( 30-90%)
References:
Very good
What is meant by bioavailability of a drug?
What is the implementation of bioavailability on planning the dose of the following immunosuppressive drugs?
A -TACROLIMUS
Drug interactions with CNI
A- Enzyme inhibitors increase level of CNI:
B- Enzyme inducers decrease level of CNI:
B-MMF
C-CYLOSPORINE,
D-AZATHIOPRINE,
REFEERENCES
1-Nasrullah A. Undre.Pharmacokinetics of tacrolimus-based combination therapies.Nephrol Dial Transplant (2003) 18 [Suppl 1]: i12–i15.DOI: 10.1093/ndt/gfg1029.
2-Hyunyoung Jeong* and Bruce Kaplan†.Therapeutic Monitoring of Mycophenolate Mofetil.Clin J Am Soc Nephrol 2: 184 –191, 2007. doi: 10.2215/CJN.02860806.
3-D. J. FREEMAN.Pharmacology and Pharmacokinetics of Cyclosporine.Clin Biochern, Vol. 24, pp. 9-14, 1991.
4-Gary L. C. Chan, Pharm.D., Daniel M. Canafax, Pharm.D., and Curtis A. Johnson, Pharm.D.The Therapeutic Use of Azathioprine in RenalTransplantation.Pharmacotherapy 1987;7(5):165-77. doi: 10.1002/j.18759114.1987.tb04046. https://doi.org/10.1002/j.1875-9114.1987.tb04046.
Very good
Drug bioavailability:
The extent and rate at which the active moiety (drug or metabolites) enters systemic circulation,thereby accessing the site of action.This is always measured by Area under the concentration time curve AUC.
AUC:
The effect of a medicine is measured by quantifying AUC ,which is serum concentration vs time frame.
It’s largely dependent on the properties of the dosage form,which depend partly on its design and manufacture. Therefore rout of administration is pivotal in determining the concerned bioavailability,and subsequently the dosage of medicine.
Oral administration of medicine will be subjected to the absorption by intestinal wall to the portal circulation.
First pass metabolism:
Metabolism that occurs before a drug reaches systemic circulation. Therefore, many drugs may be metabolized before adequate plasma concentrations are reached.
Low bioavailability:
1) Extensive first pass metabism as mentioned earlier.
2) insufficient time for reabsorption.
3) Gastrointestinal disorders:Malabsorption syndrome,Achlorhydria,previous GI surgery.
4) chemical reactions,
Assessment of bioavailability:
Performed by determining the area under the plasma concentration-time curve AUC. Which is comparison of plasma level of a drug given by particular rout of administration with plasma level achieved by intravenous injection.
Bioavalability of Anti-rejection medications:
Cyclosporin:
Bioavailability of Cyclosporin is variable. Ranging from 10% to 89%. Peak bio-availability occurring 1-8 hours after administration.
Tacrolimus:
Bio-availability of Tacrolimus is poor, range from 11.2-19.1%, and it’s even worse in patient awaiting transplantation. Its peak level acheived within 1.5 -2 hours after adminstration.
MMF:
It’s bioavailability,94%.As it’s rapidly absorbed in the small intestine,It’s maximum concentration reached by 60-90 minutes..
Azathioprine:
It’s bioavalability is 50-60%
Implementation in Renal Transplantation:
1)As far as the bioavailability of CNI is poor ,especially for Tacrolimus, both of the CNI have to be administered intravenously in early pre and post transplantation to achieve a therapeutic level.
2) because of AUC spanning over few hours, 2 separate doses of CNI have to be administered.
3) Due to the variable range of intestinal absorption and therefore of AUC thereof,trough blood level has to be relied on in determining the dose of CNI.
4) The constant level of bioavailability and peak level of MMF , and make measurment of its trough level unnecessary in the daily practice. .
5) Similarly, MMF rapid absorption and peaking level ,make it mandatory to administered twice daily.
6) The same concerns applied to AZA,as it’s constantly absorbed with expected trough level and peak level..
References:
1)Gary price;Deven A.Patel.Drug bioavailability, September 2021 university of Tennnessee health science center.
2)Drug Bioavailability,Comprehensive Medical ChemistryII ,2007.
Very good
Bioavailability is a term that includes both the extent and rate of drug absorption . The extent of drug absorption (F) represents the fraction of the administered amount of drug that reaches the peripheral circulation in its active form.
Bioavailability of immunosuppressive drugs:
1-Mycophenolate mofetil (MMF, CellCept): Oral bioavailability :80.7% (renal transplant patients) 94% (healthy volunteers)
*Effect of food in absorption: High-fat meal: ↓Cmax by 40%; AUC is unchanged
-Should be taken on an empty stomach or at a consistent time each day in relation to meals to improve GI tolerability
-Giving total daily dose in three or four equally divided doses may improve GI tolerability
*Half-life in hours: 17.9 (11.4 to 24.4)¶ (MPA): the inactive metabolite mycophenolic acid glucuronide MPAG can accumulate in renal failure. which is excreted primarily via urine
2-Mycophenolate sodium, enteric coated (Myfortic): Oral bioavailability: 72% (renal transplant patients)
*Effect of food in absorption:
High-fat meal: ↓Cmax by 33%; AUC is unchanged
Should be taken on an empty stomach
*Half-life in hours: 12 (8 to 16) (MPA): the inactive metabolite mycophenolic acid glucuronide MPAG can accumulate in renal failure. which is excreted primarily via urine
3- Cyclosporine modified (microemulsion) (Neoral): Oral bioavailability 23 to 50% better absorbed than non-modified formulation (Cyclosporine non-modified (Sandimmune) 10 to 89%) (renal transplant patients)
<10% (liver transplant patients) in renal and liver transplant patients, respectively
*Effect of food in absorption: High-fat meal: ↓ Cmax by 33% and ↓AUC by 13%
Should be taken at a consistent time each day in relation to meals
*Half-life in hours: 8.4 (5 to 18), Prolonged in hepatic impairment. inactive metabolites cleared fecally via bile
4-Tacrolimus immediate-release capsule (Prograf): Oral bioavailability: 7 to 32%
*Effect of food in absorption: High-fat meal: ↓Cmax by 77% and ↓AUC by 37%
High-carbohydrate meal: ↓Cmax by 65% and ↓AUC by 28%,Should be taken on an empty stomach
*Half-life in hours: 12 (2 to 36), Prolonged in severe hepatic impairment, inactive metabolites cleared fecally via bile
Tacrolimus extended-release capsule (Astagraf XL): Oral bioavailability: 12 to 19%
*Half-life in hours: 38 (35 to 41),Prolonged in severe hepatic impairment
5-Azathioprine: Break down to 6-mercaptopurine (6-MP).After oral administration of azathioprine, the maximum plasma radioactivity occurs at 1-2 hours with a half-life of 4-6 hours. Azathioprine is mainly excreted as 6-thiouric uric acid in the urine.
Reference: US Food and Drug Administration. Clinical drug interaction studies — Cytochrome P450 enzyme- and transporter-mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions (Accessed on June 5, 2020).
Well done concise and clear
2.Ciclosporin ;
3.MMF ;
4.Azathioprine ;
Reference ;
Hand book of Nephrology & Hypertension ; Simon Steddon & Neil Ashman
Thankyou for highlighting therapeutic window and index
Excellent
Thnxs prof