is the fraction of the administered dose of a drug that reaches the systemic circulation .For intra venous route bioavailability is 100%while in other routes of administration ,it could be lower .It may be influence by the first pass effect .
Therapeutic equivalence
indicates that drug products, when are given to the same patient at the same dosage, provide the same therapeutic and adverse effects .
Some immunosuppressant drugs such as cyclosporine, which have different products. Also, the difference between its therapeutic and toxic or ineffective concentration is small and considered to have a narrow therapeutic window .
Bioavailability is usually assessed by determining the area under the plasma concentration . The most reliable measure of a drug’s bioavailability is AUC. AUC is directly proportional to the total amount of unchanged drug that reaches the systemic circulation .
Accordingly immunosuppressant agent should be monitored by assessing their blood level .The peak level of cyclosporine (2hrs after dosing C2) may correlate better with drug exposure than trough level(C0) .The trough level (drawn immediately ,preceding the next dose) expresses an adequate drug exposure . For mTOR inhibitor ,the trough level correlate well with therapeutic effects as well . The therapeutic drug monitoring is not routinely performed in case of Mycophenolic acid .The blood level of Azathioprine cannot determine its effectiveness .
Reference ;
1. Al Ameri MN, Whittaker C, Tucker A, Yaqoob M, Johnston A: A survey to determine the views of renal transplant patients on generic substitution in the UK. Transpl Int 2011;24:770–779. [PubMed] [Google Scholar]
2. Rehman S, Wen X, Casey MJ, Santos AH, Andreoni K: Effect of different tacrolimus levels on early outcomes after kidney transplantation. Ann Transplant 2014;19:68–75. [PubMed] [Google Scholar]
3. Taber DJ, Baillie GM, Ashcraft EE, et al.: Does bioequivalence between modified cyclosporine formulations translate into equal outcomes? Transplantation 2005;80:1633–1635. [PubMed] [Google Scholar]
4. Molnar AO, Fergusson D, Tsampalieros AK, et al.: Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis. BMJ 2015;350:h3163. [PMC free article] [PubMed] [Google Scholar]
Abdullah Raoof
3 years ago
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 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
monitoring of cyclosporine and tacrolimus drug level is important part of transplantation because of interpatiiont and intrapatient variation .
there is arelation between drug level and rejection episodes . this is an area of confusion because of various assay available and different sample used ( plasma , whole blood ).
When Sandimmune was introduced, the trough level of cyclosporine (Co ), rather than the peak level(C2), was measured because its correlate better with toxic complications. More sophisticated techniques of monitoring is constructed to calculate the AUC, which reflects the bioavailability of the drug and may theoretically allow for more precise and individualized patient management. Although attractive, but costy and inconvenience.
Further studies suggest that c2 rather than c0 correlate better with clinical event.Therefore the c2 monitoring become routine .
For tacrolimus, the trough levels are usually used
for monitoring, and this level is an adequate approximation of drug exposure: some programs use peak tacrolimus levels.
Cyclosporine level can be measured in plasma or whole blood. Whole blood is the recommended specimen type
Several methods are currently available to measure cyclosporine, and each differs in specificity for parent compound. High-performance liquidchromatography (HPLC) is the most specific method for measuring unmetabolized parent cyclosporine and is considered the reference method ( but is expensive )..
Immunoassays, which use monoclonal antibodies against cyclosporine, are commonly used and have largely replaced HPLC because they can be performed on automated chemistry analyzers. The most commonly used immunoassay to measure cyclosporine in whole-blood samples is the Abbott (Chicago, IL) fluorescence polarization immunoassay (FPIA), which has significant cross-reactivity with cyclosporine metabolites and overestimates cyclosporine by as much as 45% .
For monitoring of tacrolimus concentrations, most laboratories use the Abbott monoclonal antibody-based microparticle enzyme immunoassay (MEIA) that can be performed on an automated instrument (IMx). This assay permits accurate estimation of tacrolimus levels as low as 2 ng/mL.
Abbott has also developed a chemiluminescent microparticle immunoassay (CMIA) that is available on the ARCHITECT family of instruments with a reported detection limit of less than 1 ng/mL. New methodologies employ electrochemiluminescence immunoassay (ECLIA) techniques similar to CMIA with a reported detection limit of 0.5 ng/mL utilizing a 300^L sample size.
2- Currie GM. Pharmacology, Part 2: Introduction to Pharmacokinetics. J Nucl Med Technol. 2018 Sep;46(3):221-230.
Ahmed Ziada
3 years ago
Monitoring immuno suppressive drugs level is very crucial in transplant patient especially those with Narrow safety margin like CNI and mTORi
We can measure C max and trough level to access toxicity and efficacy
Bioavailability is the percent of drug that Reach its site of action
Alyaa Ali
3 years ago
Bioavailability refers to the extent a substance or drug becomes completely available to its intended biological destination . 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.
Drug bioavailability is the fraction of the administered dose that reaches the systemic circulation. For the clinician, the most relevant consideration is the percentage of active drug that reaches the central compartment. Bioavailability does not take into account the rate at which the drug is absorbed. Bioavailability is affected by factors that influence absorption. For the majority of currently used immunosuppressive drugs, measurement of total drug exposure by determination of the dose-interval area under the concentration curve (AUC) seems to provide more useful information for clinicians in terms of concentration-exposure and exposure-response as well as reproducibility.
saja Mohammed
3 years ago
immunsuperssive therapy post transplantion very crucial to prevent rejection and maintian good immune response with better graft and patient survival ,drug monitroing also help in assess the potency of the regular immunsuppression with less side effects by using drug monitroing that will refect the optimal theraputic level with aviodnace of under supperssion or oversuppression,CNI trough otr C2 level to monitor the tacrolimus orcyclsoprine trough level ,sirolimus , everolimus trough Drug bioavailability refere to the rate and range of active molecule absorption, when it becomes available in the systemic circulation or at the site of drug action, respectively. Drug bioavailability after oral administration is affected by many 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
Ofonime Udoh
3 years ago
Immunosuppression drugs [immunosuppresants] are impotant in transplant medicine as they reduce the incidence of organ rejection, acute and chronic, in transplant recipients.These medicines must be in the right concentration in the recipient, as subtherapeutic doses can cause rejection, and supra-therapeutic levels are toxic to the organs and predispose to infections. These medicines have a narrow therapeutic index, and have differing inter-individual variability, and as a result require monitoring. Factors that can cause inter-individual variability include gender, body mass, drug-nutrient interactions, drug-disease interactions, infection.
Imunosupressants are monitored nby therapeutic drug monitoring [TDM]. TDM is themeasurement and interpretation of the concentration of these drugs in t biological fluids, with the aim of predicting oprgan responses. They are part of transplant protocols.TDM is done for Tacrolimus, Sirlimus, Mycophenolate mofetil and cyclosporine.
Bioavability [of a drug] is the extent and rate at which the active moiety of the drug or its metabolite, enters the systemic circulation and is thus able to access the site of action. Bioavailability ois greatly determined by the properties of the dosage form, and these properties depend on the manufacture and design of the medicine. Several factors can affect bioavailabity of a drug, thus causing low availability of the medicine, and they include age, gender, oral dosage form of a medicine, physicalactivity, stress disorders, and transit time in the gut.
Wallemacq PE. Therapeutic monitoring of immunosuppressant drugs. Where are we? Clinical Chemisty and Laboratory Medidine Journal. June 2005
Sukhpreet, Tiwari P. Therapeutic drug monitoring of immunosuppressants: An overview. Indian J Pharmacol 2007;39:66-70
Ahmed Omran
3 years ago
CALCINURINE INHIBITORS;TACROLIMUS OR CYCLISPORINE LEVELS NEED ROUTINE MONITORING .TACROLIMUS WHOLE BLOOD LEVEL IS MONITORED BY 12 -HOUR TROUGH CONCENTRATION FOR IMMEDIATE-RELEASE FORM AND 24 HOUR TROUGH CONCENTRATION FOR EXTENDED RELEASE ONES.TARGET LEVELS IN PATIENTS RECIEVING ANTITHYMOCYTE DEPLETION ARE 7-10 ng/mL FOR THE FIRST MONTH FOLLOWING Tr AND3-7 ng/mL FOR THE NEXT MONTHS.FOR THOSEWHO DID NOT RECIEVE ANTITHYMOCYTE DEPLETION,TARGET LEVELS ARE 8-10 ng/mL FOR THE FIRST 3 MONTHS AFTER Tr AND 3-7 ng/mLFOR NEXT MONTHS.
IN PATIENTS ON CYCLOSPORINE,WHOLE BLOOD 12 HOUR TROUGH CONCENTRATION IS ESTIMATED.TARGET LEVELS ARE 200-300 ng/mL IN FIRST 3 MONTHS FOLLOWING Tr&50-150 ng/mL FOR NEXT MONTHS.
PATIENTS RECIEVING AZATHIOPRINE WITH SIGINICANT BONE MARROW SUPPRESSION,THE ENZYME THIOPURINE METHYLTRANSFERASE IS TESTED AND IF ITS DEFICIENCY DETECTED,THE DRUG SHOULD BE DISCONTINUED.
MMF IS DISCONTINUED IN CASE OF PERSISTENT DIARRHOEA.CURRENTLY,NO LAB MONITORING AVAILABLE FOR ANTIMETABOLITE AGENTS.
BIOAVAILABILITY:
IT DESCRIBES THE STATE OF COMPLETE AVAILABILITY OF SUBSTANCE OR MEDICATION FOR THE TARGET SITE OR SITE OF DESIRED ACTION.IT COULD BE DEFINEDAS THE UNCHANGED ACTIVE FORM OF A DRUG THAT REACHES SYSTEMIC CIRCULATION WITH THE ASSUMPTION THAT 100% OF THE ACTIVE DRUG IN CIRCULATION WILL REACH ITS TARGET SITE.INTRINSIC FACTORS AFFECTING BIOAVAILABILITY INCLUDE ACTIVATION METABOLISM,DRUG RECEPTORS,ABSORPTIONAND ROUT OF ADMINSTRATION.EXTRINSIC FACTORS INCLUDE INTERACTION WITH OTHER DRUG OR FOOD.
REFERENCES:
KIDIGO CLINICAL PRACTICE GUIDELINES FOR THE CARE OF KIDNEY TRANSPLANT RECIPIENTS ,Am J Transplant ,2009;9 suppl 3;s1
Schiff J,Cole E, Cantarovich M, Therapeutic monitoring of calcinurine inhibitors for the nephrologist .Clin J Am Soc Nephrol,2007;2;374
Chow SC,BIOAVAILABILITY AND BIOEQUIVALENCE IN DRUG DEVELOPMENT,WILEY INTERDISCIP REV COMPUT STAT,2014;6(4):304-312
Mansoor A,Mahabadi N.stat pearls treasure island:JUL 26,2021,VOLUME OF DISTRIBUTION.9 (Pub Med)
Amer Hussein
3 years ago
Bioavailability (F) is defined as the rate and extent to which the active constituent or active moiety of a drug is absorbed from a drug product and reaches the circulation
Azathioprine, steroids, anti-lymphocyte globulin, and OKT3Monitoring the blood or plasma concentration of these drugs is not considered worthwhile as they all have relatively wide therapeutic indices. The three agents are generally given in fixed doses and are not subjected to therapeutic drug monitoring.
cyclosporine is monitored by A trough level is the lowest concentration reached by a drug before the next dose is administered. For example, if cyclosporine is given twice a day, a blood sample is usually drawn 12 hours after the last dose, before a new dose is given. Tacrolimus is usually taken twice a day at set intervals before or after meals. When a person takes a dose, blood concentrations rise and peak within about 2 to 3 hours and then begin to slowly drop. The blood test is usually measured as a ‘trough’ level.
Mina
3 years ago
■Bioavailability refers to the extent and rate at which the active moiety of a drug 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.
■Causes of low bioavailability :
1-Many drugs may be metabolized before adequate plasma concentrations are reached.
Orally administered drugs must pass through the intestinal wall and then the portal circulation to the liver, both are common sites of firstpass metabolism (metabolism that occurs before a drug reaches systemic circulation).
Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs.
2- Insufficient time for absorption in the gastrointestinal (GI) tract is a common cause of low bioavailability.
If the drug does not dissolve readily or cannot penetrate the epithelial membrane (for example if it is highly ionized and polar), time at the absorption site may be insufficient.
In such cases, bioavailability tends to be highly variable as well as low.
3-Chemical reactions that reduce absorption can decrease bioavailability
4- Others :
Age, sex, physical activity, genetic phenotype, stress, disorders (eg, achlorhydria, malabsorption syndromes), or previous GI surgery (eg, bariatric surgery) can also affect drug bioavailability.
■ASSESSING the bioavailability:
Bioavailability is usually assessed by determining the area under the plasma concentration–time curve (AUC).
The most reliable measure of a drug’s bioavailability is AUC.
AUC is directly proportional to the total amount of unchanged drug that reaches systemic circulation.
Bioavailability determinations based on the peak plasma concentration can be misleading because drug elimination begins as soon as the drug enters the bloodstream.
Peak time (when maximum plasma drug concentration occurs) is the most widely used general index of absorption rate; the slower the absorption, the later the peak time.
For drugs excreted primarily unchanged in urine, bioavailability can be estimated by measuring the total amount of drug excreted after a single dose
_________________________________
●●☆☆IMMUNOSUPPRESSION MONITORING☆☆●●
Regarding
1- CNI :
TACROLIMUS :
Monitoring Parameters
Renal function, hepatic function, serum electrolytes (calcium, magnesium, phosphorus, potassium) periodically in patients with heart failure, bradyarrhythmias, or concomitant medications known to prolong the QT interval),
blood glucose (frequently).
Monitor BP (3 times/week for first few weeks, then gradually decrease frequency as patient stabilizes).
Patients receiving IV tacrolimus should be monitored for signs/symptoms of hypersensitivity/anaphylactic reactions for at least the first 30 minutes following the start of the infusion, and frequently thereafter.
Monitor for QT prolongation; consider echocardiographic evaluation in patients who develop renal failure, electrolyte abnormalities, with heart failure, bradyarrhythmias, or concomitant medications known to prolong the QT interval or clinical manifestations of ventricular dysfunction.
Monitor for signs/symptoms of infection, neurotoxicity, and secondary malignancy.
Closely monitor tacrolimus levels to assist in dose adjustment, monitor compliance, prevent organ rejection, and reduce drug-related toxicity.
Whole blood concentrations should be used for monitoring (trough for oral therapy drawn typically within 30 minutes prior to the next dose) frequency varies depending on transplant type, time since transplantation, and clinical situation.
NB in renal as well as liver tx ptns :
Tacrolimus serum levels may be falsely elevated in infected liver transplant patients due to interference from
beta-galactosidase antibodies.
●☆☆Reference Range in renal Tx: ☆☆●
Whole blood trough concentrations:
■Immediate release:
In combination with azathioprine (if used):
Months 1 to 3: 7 to 20 ng/mL.
Months 4 to 12: 5 to 15 ng/mL.
In combination with mycophenolate mofetil/IL-2 receptor antagonist (eg basiliximab):
4 to 11 ng/mL.
In combination with mTOR inhibitor (everolimus):
4 to 8 ng/mL for the first 2 months post-transplant
followed by
3 to 5 ng/mL thereafter (Sommerer 2016).
■■Extended release (Astagraf XL):
Adult:
●With basiliximab induction:
Month 1: 7 to 15 ng/mL.
Months 2 to 6: 5 to 15 ng/mL.
>6 months: 5 to 10 ng/mL.
●Without basiliximab induction:
Month 1: 10 to 15 ng/mL.
Months 2 to 6: 5 to 15 ng/mL.
>6 months: 5 to 10 ng/mL.
●●CYCLOSPORIN●●
Monitor plasma concentrations, renal function (serum creatinine and BUN), and blood pressure periodically and following the addition, modification, or deletion of other medications.
Monitor for hypersensitivity reactions (IV cyclosporine). Monitor for signs/symptoms of hepatotoxicity, secondary malignancy, diabetes mellitus, infection.
Monitor for progressive cognitive or motor deficits; magnetic resonance imaging may be required for diagnosis of posterior reversible encephalopathy syndrome (PRES).
Rtx that presented with Nephrotic syndrome ( these data is for nephrotic syndrome in general ):
Baseline blood pressure (2 readings within 2 weeks), fasting serum creatinine (at least 3 levels within 2 weeks), creatinine clearance, urinalysis, CBC, liver function, serum uric acid, serum potassium, and malignancy screening (eg, skin, mouth, lymph nodes).
Biweekly monitoring of blood pressure for initial 3 months and then monthly thereafter, frequent monitoring of renal function and periodic cyclosporine trough levels are recommended during therapy.
Consider renal biopsy in patients with steroid dependent minimal change nephropathy who have been maintained on therapy >1 year.
Therapeutic trough range in solid organ transplant (kidney, liver, heart): Not absolutely defined, dependent on organ transplanted, time after transplant, organ function and CsA toxicity:
General range of 100 to 400 ng/mL; refer to institutional protocol for specific therapeutic ranges
Toxic level: Not well defined, nephrotoxicity may occur at any level
Recommended cyclosporine therapeutic ranges when administered in combination with everolimus for renal transplant (Zortress product labeling 2018):
Month 1 post-transplant: 100 to 200 ng/mL
Months 2 and 3 post-transplant: 75 to 150 ng/mL
Months 4 and 5 post-transplant: 50 to 100 ng/mL
Months 6 to 12 post-transplant: 25 to 50 ng/mL
☆●☆Alternative monitoring (renal transplant): Two-hour post cyclosporine dose level (obtaining a level 2 hours after administration correlates well with drug exposure throughout the 12-hour dosing interval [Schiff 2007])
IL-2 induction therapy (2-hour post cyclosporine dose level):
Month 1 and 2: >1,500 ng/mL
Month 3: 1,200 to 1,400 ng/mL
Month 4 to 12: 600 to 1,000 ng/mL
Month >12: ~800 ng/mL
Antithymocyte globulin (rabbit) induction therapy (2-hour post cyclosporine dose level):
Month 1 to 3: 1,000 to 1,200 ng/mL
Month 4 to 12: 600 to 1,000 ng/mL
Month >12: ~800 ng/mL
In most patients treated with cyclosporine, we monitor whole-blood 12-hour trough (C0) concentrations [4]. With this approach, our C0 target levels are the following:
●200 to 300 ng/mL in months 1 to 3 after transplantation
●50 to 150 ng/mL for subsequent months
Although monitoring of trough levels (12 hours postdose) of cyclosporine is common practice, there is a poor correlation between clinical outcome and drug exposure as assessed using this strategy. Thus, in some patients (eg, patients suspected of having poor cyclosporine absorption), we monitor two-hour postdose cyclosporine (C2) levels [63]. Among kidney transplant recipients, the C2 level may correlate more closely with exposure, with higher C2 concentrations being associated with decreased acute rejection rates in the first year posttransplant [64-66]. However, C2 monitoring is often more difficult and less convenient for the patient. Our C2 target levels are the following:
●800 to 1000 ng/mL in months 1 to 3 after transplantation
●400 to 600 ng/mL for subsequent months
MMF and EC-MPS are similar in efficacy and safety [68,69].
We prefer EC-MPS over MMF because EC-MPS may be associated with fewer gastrointestinal side effects among certain groups of patients (eg, patients with indigestion, diabetes, those treated with glucocorticoids, or patients converted from MMF to EC-MPS between 6 to 12 months posttransplant)
MMF is now the best antimetabolite used to minimize rejection according to 2009 KDIGO guidelines.
However, we do not use mycophenolate in female recipients of childbearing age unless they are on long acting contraception, have undergone surgical sterilization procedures, or have absolute infertility. Mycophenolate is teratogenic, and its use is contraindicated in pregnancy.
Thus, in these patients, we prefer to use azathioprine, which does not seem to have a detrimental effect on fertility or pregnancy.
■■ AZATHIOPRINE
The usual maintenance dose for azathioprine is 1.5 mg/kg per day, although it is 2.5 mg/kg at some centers.
CBC with differential and platelets (weekly during first month, twice monthly for months 2 and 3, then monthly thereafter; monitor more frequently with dosage modifications), total bilirubin, liver function tests (every 3 months), CrCl, monitor for signs/symptoms of infection and malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss).
Azathioprine has been associated with skin cancer with long-term use after kidney transplantation.
Patients taking azathioprine for a prolonged time period should avoid sun exposure and be monitored for skin cancer regularly.
Thiopurine S-methyltransferase (TPMT) genotyping or phenotyping: Consider testing for TPMT deficiency, particularly in patients with abnormally low CBC unresponsive to dose reduction. TPMT genotyping or phenotyping may assist in identifying patients at risk for developing toxicity (CPIC [Relling 2019]).
Nudix hydrolase 15 (NUDT15) genotyping: Consider genotyping for NUDT15 deficiency in patients who experience severe bone marrow toxicities or repeated myelosuppressive episodes. NUDT15 genotyping may assist in identifying patients at risk for developing toxicity (CPIC [Relling 2019]).
■■GLUCOCORTICOIDS
Monitoring to:
• BP
• weight
• serum glucose
• Electrolytes
• Growth in pediatric patients
•Presence of infection
• Bone mineral density
• Assess HPA axis suppression
(eg, ACTH stimulation test,
morning plasma cortisol test,
urinary free cortisol test),
•Hgb
•Occult blood loss
•Chest x-ray (at regular
intervals during prolonged
therapy)
•IOP with therapy >6 weeks, eye examination (periodically during therapy [AASLD (Mack 2020)]).
■■ATG ( RABBIT)
Monitoring Parameters
Lymphocyte count (total lymphocyte and/or T-cell subset), CBC with differential and platelet count; vital signs during administration; signs and symptoms of infection
Solid organ transplant: Absolute CD3 count (cells/µL) monitoring and CD3 based dosing has been considered in renal and heart transplant recipients. It may be beneficial in certain patient populations but is not routinely recommended or utilized. Dose adjustments have been recommended based on the CD3 count (Krasinska 2002).
■■Rituximab :
Monitoring Parameters
•CBC with differential and platelets (obtain prior to treatment and prior to each treatment course, and at weekly to monthly intervals and more frequently in patients with lymphoid malignancies, or at 2- to 4-month intervals in rheumatoid arthritis patients, granulomatosis with polyangiitis and microscopic polyangiitis).
•Continue to monitor for cytopenias after the final rituximab dose and until resolution.
•Monitor electrolytes (in patients at risk for tumor lysis syndrome [TLS]), renal function (in patients at risk for TLS or nephrotoxicity), fluid/hydration status balance. •Monitor BP and vital signs.
•Hepatitis B virus reactivation screening: Screen all patients for hepatitis B virus (HBV) infection prior to therapy initiation (eg, hepatitis B surface antigen [HBsAG] and hepatitis B core antibody measurements).
•Screen patients with multiple sclerosis for latent infections (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline). In addition, carriers and patients with evidence of current infection or recovery from prior hepatitis B infection should be monitored closely for clinical and laboratory signs of HBV reactivation and/or infection during therapy and for up to 2 years following completion of treatment.
•The American Society of Clinical Oncology HBV screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with HBsAg, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results.
Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring and follow-up. Monitor for signs of active hepatitis B infection.
•••Monitor closely for infusion-related reactions.
•Perform cardiac monitoring during and after rituximab infusion (in rheumatoid arthritis patients and in patients with preexisting cardiac disease, a history of arrhythmia or angina, or if clinically significant arrhythmias develop during or after subsequent infusions). Monitor for signs/symptoms of bowel obstruction/perforation (abdominal pain, vomiting), tumor lysis syndrome, and/or mucocutaneous skin reactions. Monitor for signs or symptoms of progressive multifocal leukoencephalopathy (focal neurologic deficits, which may present as hemiparesis, visual field deficits, cognitive impairment, aphasia, ataxia, and/or cranial nerve deficits); if progressive multifocal leukoencephalopathy is suspected, obtain brain MRI scan and lumbar puncture.
It is clearly known than all patient after transplantation should be on immunosuppressants for maintaining their graft functioning . Immunosuppressants require therapeutic drug monitoring because of their narrow therapeutic index and significant inter-individual variability in blood concentrations. This variability can be because of factors like drug-nutrient interactions, drug-disease interactions, renal-insufficiency or inflammation . Drug monitoring is widely practiced especially for cyclosporine, tacrolimus, sirolimus and mycophenolic acid.
1. Cyclosporine
Therapeutic monitoring of immunosuppressive therapy with cyclosporine is a critical requirement because of intra- and inter-patient variability of drug absorption, narrow therapeutic window and drug induced nephrotoxicity.
Mycophenolic acid (MPA)
Some reasons for therapeutic drug monitoring of MPA during post-transplant period include: relationship between MPA pharmacokinetic parameters and clinical outcomes, Inter-patient pharmacokinetic variability for MPA despite fixed MMF doses, alternations of MPA pharmacokinetics during the first months after transplantation, drug- drug interaction and influence of kidney function on MPA pharmacokinetic.
Sirolimus
A recent review of the pharmacokinetics of sirolimus suggested a therapeutic range of 5 to 10 μg l−1 in whole blood. However, the only consensus guidelines published on the therapeutic monitoring of sirolimus concluded that there was not enough information available about the clinical use of the drug to make recommendations.
Tacrolimus
Sudies have shown, in kidney and liver transplant patients, significant associations of low tacrolimus concentrations with rejection and of high concentrations with nephrotoxicity. Although the feasibility of a limited sampling scheme to predict AUC has been demonstrated, as yet, trough, or pre-dose, whole blood concentration monitoring is still the method of choice.
Bioavailability
Is defined as the extent a substance or drug becomes completely available to its intended biological destination. 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 in other words , bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered. This definition assumes 100% of the active drug that enters systemic circulation will successfully reach the target site.
References
Spector R, Park GD, Johnson GF, Vesell ES. Therapeutic drug monitoring. Clin Pharmacol Ther. 1988;43:345–353. [PubMed
1.
Currie GM. Pharmacology, Part 2: Introduction to Pharmacokinetics. J Nucl Med Technol. 2018 Sep;46(3):221-230. [PubMed
Mahmoud Rabie
3 years ago
Bioavailability of a drug means the fraction of this medication that reaches the systemic circulation. For example the bioavailability of intravenous drugs is 100% while bioavailability in other routes is less due to the effect of first pass metabolism and intestinal absorption.
Due to the narrow therapeutic index of the immunosuppression drugs and drug drug interactions, they should be monitored by therapeutic drug monitoring (TDM), which means frequent measuring of drug level in the blood.
Examples for drugs that should be monitored include cyclosporine, MMF, Tacrolimus, Sirolimus.
To demonstrate the importance of TDM of these drugs, Tacrolimus for example , high concentration is associated with nephrotoxicity while low concentrations is associated with increased risk of rejection.
Kidney transplant recipients need appropriate maintenance immunosuppression to preserve their graft. Under-immunosuppression or over- immunosuppression are associated with high rate of rejection or infection and malignancy, respectively. Proper immunosuppression needs proper dose of drug. But because of inter or intra-variability among people or different forms of immunosuppression drug, it is difficult to reach. For this purpose, tandem drug monitoring is performed after transplantation based on time after Tx at regular intervals. Trough level is used for Tacrolimus, Sirolimus and Everlimus. For cyclosporine, C2 is performed in addition to C0 and is better.
Bioavailability means level of drug that enters into circulation and at the site of action of drug. Bioavailability of an oral dose of drug is determined by comparison with IV administration of the same drug. This topic is important when using generic immunosuppression drugs instead of original brand because of their price. MMF is usually administered at fix dose without measurement of its drug level. New methods to avoid over-immunosuppression such as torque teno virus (TTV) load or virus-specific T cells (Tvis) level can be used especially in children.
References:
1. Ahlenstiel-Grunow, T., Pape, L. Novel ways to monitor immunosuppression in pediatric kidney transplant recipients—underlying concepts and emerging data. Mol Cell Pediatr 8, 8 (2021).
2.Tsipotis E, Gupta NR, Raman G, Zintzaras E, Jaber BL. Bioavailability, Efficacy and Safety of Generic Immunosuppressive Drugs for Kidney Transplantation: A Systematic Review and Meta-Analysis. Am J Nephrol. 2016;44(3):206-18.
Last edited 3 years ago by Nasrin Esfandiar
Mohammed Sobair
3 years ago
Immunosuppressive drugs used to reduce immune response.
Common transplant immunosuppression drugs are:
1-Glucocorticoid.
2—Calcineurin inhibitor.
3-Antimetabolic agent.
4-Biological agent.
These drugs are effective at therapeutic dose but variation exist with their narrow
therapeutic dose which can lead to adverse effect.
Therapeutic drug monitoring is needed to check for concentration, that’s not too low or
high, with risk of infectivity with low and toxicity with high dose. In therapeutic drug
monitoring plasma concentration is measured and dose adjusted to achieve goals.
This monitoring with blood concentration done with following drugs of response and side
effect in addition to vital sign and basic blood chemistry ,i.e. CBC ,RBG ,RFT AND LFT.
As some drugs cause bone marrow suppression. , anemia, renal impairment and liver
failure.
Cyclosporine :TDM
1-Troughh concentration:
Most transplant center use A CSA concentration either C0 predose trough or 2hours post
dose.
2-Area under the curve (AUC):
MULTPLE MEASURMENT NEEDED, TIME CONSUMMING.
3-Two hours post dose concertation (C2):
More simple by measuring blood CSA concentration at 2hours after dose.
4-Bayesian forecasting:
Calculate dosage regimens and pharmacokinetic parameters and predict drug
concentration by blending population value with patient specific values.
The therapeutic level serum concentration is 50-150 ng/ml.
Tacrolimus (TRL):
Therapeutic rang for TRL in most transplant center is 5-20ng/ml in blood.
Trough or predose whole blood concentration is used (12hours after previous dose).
Mycophenolic acid (MPA):
Though current labeling information for MMF does not indicate any need for therapeutic
monitoring of plasma MPA, there’s difference in protocol in transplant center, depend on
availability of monitoring, in high risk patient or those with adverse effect.
With trough concentration, plasma concentration of MPA measured immediately before
dose.
Sirolimus (SRL):
The appropriate SRL trough concentration at steady state (Cmin, SS).
Measurement should be done after 4days after induction or change of therapy..
After monitor Cmin, SS weekly for first month and biweekly for the next month, targeting
5 to 15mg/l.
Everlimus (EVL):
The EVL, Cmin is good surrogate for EVL.
Recommended therapeutic range for EVK is trough concentration of 3-8ng/ml.
Azathioprine:
monitoring the blood or plasma concentration of these drugs is not considered
worthwhile as they all have relatively wide therapeutic indices. The three agents are
generally given in fixed doses and are not subjected to therapeutic drug monitoring.
However, a case can be made for the measurement of the activity of the enzyme
thiopurine methyl transferase (TPMT) as an adjunct to azathioprine therapy.(2).
Daclizumab and basiliximab:
Due to wide therapeutic index, little to be gained from therapeutic drug monitoring for these agents (3).
Bioavailability:
Is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered (4).
Reference:
1-Ana Luisa Robles .Minarda De La Arciniega et al, Clinical pharmacology and
therapeutic drug monitoring of immunosuppressive Agent, Feb.DOI, 105772/54910.
How to monitor immunosuppression medications
Tranplantation successful management depends on strong knowledge with immunosuppressant medications and its side effects
The conventional triple immunosuppressive medications are steroids,mmf and tacrolimus
With or without induction upon certain indication which either depleting (ATG)Or non depleting (basilixmab)
Bentata, Y. (2020). Mycophenolates: The latest modern and potent immunosuppressive drugs in adult kidney transplantation: What we should know about them?. Artificial organs, 44(6), 561-576.
Barry D Kahan 1, Paul Keown, Gary A Levy, Atholl Johnston, Therapeutic drug monitoring of immunosuppressant drugs in clinical practice. 2002 Mar;24(3):330-50
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
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
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
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
Esmat MD
3 years ago
Bioavailability is a term used for the percentage or the fraction (F) of the administered dose of a drug that reaches the systemic circulation. Bioavailability is practically 100% following intravenous administration but it could be lower for other routs such as oral or dermal. Bioavailability may be influenced by the first pass effect (metabolizing effect of organs through which drug passes before reaching the systemic circulation, properties of dosage forms, and different formulations of a given drug.
Therapeutic equivalence is another term that indicates that drug products when are given to the same patient at the same dosage, provide the same therapeutic and adverse effects. It is especially important for some immunosuppressive drugs such as cyclosporin which have different products. In addition, the difference between its therapeutic and toxic or ineffective concentration is small and considered to have a narrow therapeutic window. Bioavailability is usually assessed by determining the area under the plasma concentration–time curve. The most reliable measure of a drug’s bioavailability is AUC. AUC is directly proportional to the total amount of unchanged drug that reaches systemic circulation.
For example, the bioavailability of microemulsion formulation (Neoral) is better than sandimmune. Bioavailability of oral administered cyclosporin is 30%-45% of intravenous infusion, And sublingual dosing of tacrolimus is one half of that required for the oral administration.
Measuring of the blood level of immunosuppressive agents is utilized for monitoring them. For Neoral cyclosporin, its peak level, typically 2 hours after dosing (C2) may correlate better with drug exposure than its trough level (C0). for Tacrolimus, trough level (drawn immediately preceding the next dose expresses an adequate drug exposure. For mTOR inhibitors, the trough level correlate well with therapeutic effects as well.
For Mycophenolic acid, therapeutic drug monitoring is not routinely performed, and the blood level of Azathioprine is not valuable, because its blood level can’t determine its effectiveness.
Immunosuppressant drugs should be closely monitored to achieve the balance state between drugs efficacy and their side effects.
Most clinicians used therapeutic drug monitoring TDM to monitor drug concentration and to avoid adverse effects of these drugs on the transplanted patients.
Overdose (supratherapeutic) concentration make the patient on infection risk due to over immunosuppression while low dose (sub therapeutic) put the patient in a risk of graft loss .
Many factors that affecting level of concentration such as using other drugs (drug interactions) ,sex, infection, liver diseases and renal impairment .
Most common drugs that are used in kidney transplantation and need TDM are : cyclosporine ,mycophenolate mofitile ,tacrolimus and sirolimus .
Drug bioavailability refers to the rate at which the active form of the drug enters the systemic circulation ,it’s determined by dosage and route of administration.
In summary drug bioavailability refers to the rate of active form of the drug reaches the target site of action .
Fatima AlTaher
3 years ago
Monitoring of immunosuppressive drugs after kidney transplantation is critical to achieve therapeutic level and avoid drug toxicity .Itis involves both clinical and therapeutic monitoring 1- ATG : clinical monitoring for signs of cytokine release or allergic reaction As well as monitoring level of CD3 to adjust the dose (not universally agreed). 2- Tacrolimus : through monitoring 12 h through level in serum 3- Cyclosporine through C2 ( serum drug level 2 h after the dose) (1) Drug bioavailability : define as a measurement of the rate and fraction of the initial drug dose that succeed to reach site of drug action or the body compartment where the drug can be monitored. (2) 1- Holt, D. W. (2002). Therapeutic drug monitoring of immunosuppressive drugs in kidney transplantation. Current opinion in nephrology and hypertension, 11(6), 657-663. 2- Price, G., & Patel, D. A. (2020). Drug Bioavailability.
Nazik Mahmoud
3 years ago
The calcineurin inhibitors monitored in a meticulous way to ensure the drug level was enough to prevent rejection.
Cyclosporine monitor in two way Cmin which the sample drawn immediately preceding the next dose or C2 when the sample withdrew 2 hours after the dose.
Tactolimus followed by trough level .
The bioavailability mean the concentration of the drug rich the circulation after administration; here it reflect as The area under the curve (AUC).
Wessam Moustafa
3 years ago
Monitoring immunosuppressive treatment is through therapeutic drug monitoring.
TDM is used with drugs that have narrow therapeutic index and interpersonal variability .
TDM is very important in transplantation in order to ensure least toxic dose of the drug is used , to maintain efficacy and to reduce side effects
There are two main methods for determination of immunosuppressive drugs in transplant patients: immunoassays and liquid chromatography-based methods (high-performance liquid chromatography (HPLC)
Traditionally most laboratories use immunological methods but Due to cross-reactions with some metabolites of these drugs, overestimation of the concentrations is a major problem in immunological techniques
Ciclosporin :
Whole blood concentration of the drug is used.
Could be measured pre dose ( trough level ) ,or 2hourse after the dose ( C2, C max )
Recent studies have shown that C2 reflects more actual exposure to ciclosporin .
HPLC is considered the gold standard for measuring of ciclosporin levels
Tacrolimus
Whole blood concentration is used.
is recommended that TAC be monitored at 12 hour trough levels ( C0) just before morning dose administration
the relationship between C0 and clinical outcomes is still unclear.
MMF
Trough levels are not widely used although interpersonal variability in pharmacokinetics of MMF
MMF can’t be measured in plasma at any time after oral administration, because they are rapidly metabolized .
Previously no studies have shown that its concentration correlates either to toxicity or rejection, but recently studies showed that there is some relation with clinical outcomes
Sirolimus
The predose concentrations are generally targeted in the range 4-12 μg/l when sirolimus is used with CsA or tacrolimus.
References
Wallemacq P, Armstrong VW, Brunet M, et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference. Ther Drug Monit. 2009 Apr;31(2):139–52. http://dx.doi.org/10.1097/FTD.0b013e318198d092.
Bioavailabilty means the ability of a drug to be absorbed and utilised by the body
cyclosporine
bioavailability after oral dose-30-45%
absorption is increased by food
oral dose- 7mg/kg in 2 divided doses
pediatric dose- as above
iv dose- one third of oral dose infused over 2 hours twice daily.
therapeutic monitoring
AUC is ideal but impractical as multiple blood sample collection involved and complex formulae.
C0 level corelates poorly with AUC- but still widely used .
C2 level correlates better with AUC- target C2 levels cannot be achieved in 20-40% pts,practical difficulty in obtaining accurate samples.
therapeutic drug monitoring
C0 levels correlate poorly with AUC
there is little compelling evidence to support routine MPA therapeutic monitoring as measuring MPA AUC is complex.
bioavailability
When a medicine is given intravenously, its bioavailability is 100 percent by definition. However, because of intestinal endothelial absorption and first-pass metabolism, a medication’s bioavailability is generally reduced when delivered by methods other than intravenous.
mathematically
bioavailability= AUC for extra vascular formulation/ AUC for intravscular formulation.
Various methods of TDM are available older immunoassay (IA)-based methods- microparticle enzyme IA (Abbott Diagnostics, Chicago, IL, USA), and enzyme multiplied IA (EMIT, Dade Behring, Glasgow, DE, USA) they are not so accurate, there is interference with other substances, they measure inactive metabolite, and their limit of detection is not wide.
recent liquid chromatogram (LC) based- liquid chromatogram mass spectroscopy or LC-tandem mass spectroscopy. costly, labor intensive, and require good technical support
Newer IAs chemiluminescent microparticle IA (Abbott Diagnostics) and Quantitative Microsphere System (QMS™, Thermo-Fisher) functional sensitivity <1 ng/ml overcome the disadvantages of older IAs
Several strategies for TDM of Tac
C0
C2
C3
C4
LSS in which instead of using multiple samples,only 2 or 3 samples are taken and AUC calculated.
Therapeutic drug monitoring of tacrolimus in kidney transplantation
Shyam Bihari Bansal
Therapeutic monitoring of the immunosuppression drugs is critical in the management of patients receiving kidney transplantation. As to offer adequate exposure to the drug and to prevent drug toxicity that can even affect graft function.
All drugs except (Mycophenolic acid), are primarily metabolized by the CYP3A system in the liver, and many drugs can induce these enzymes and ultimately affect the immunosuppression drug levels.
There are inter-patients variabilities related to food, drugs use, genetic (whether highly accelerator or not).
The principal approach to the measurement of CNI and Tacrolimus has been and remains immunoassays. Cyclosporine (CNI):
C0 Sample taken 12 hrs after the previous dose and just before the coming dose.
C2 after 2 hrs from the dose. And comprehensive guideline on the implementation of C2 monitoring has been developed. The rationale for its use comes from that most of the variability in the 12 hr AUC can be explained using the first four hours of the observation curve (AUC 0 – 4) and C2 is a good surrogate for AUC 0 – 4 . also reaching the C2 target concentration early after transplantation has a better effect on graft rejection, whereas the time to reach C0 target values has no apparent impact. Tacrolimus
Almost all centers depend on C0 measurement. Because it gives a good reflection to AUC.
Tacrolimus is the more effective drug for the prevention of acute rejection. Sirolimus
There is good correlation between C0 conc and AUC
Target concentrations are lower using the current chromatography assay.
Mycophyenolic acid :
Generally, fixed-dose administration of this drug is used. There is an interest in plasma concentration-guided dosing.
Bioavailability:
Reflect the percent of the drug which reaches circulation after its administration. Intravenous administration has 100% bioavailability.
Reference:
1. Holt DW. Therapeutic drug monitoring of immunosuppressive drugs in kidney transplantation. 2002;
2. Lim MA, Kohli J, Bloom RD. PT SC. Transplant Rev [Internet]. 2016; Available from: http://dx.doi.org/10.1016/j.trre.2016.10.006
Heba Wagdy
3 years ago
therapeutic monitoring of immunosuppression is important to avoid toxicity and maintain adequate immunosuppression
Cyclosporine: monitored using
C0 (12 hour trough level): common but has poor correlation with safety & drug exposure
C2 (2 hour post dose): correlate more with drug exposure and clinical events
Tacrolimus: monitored using
trough concentrations: adequate indicator of drug exposure
Sirolimus:
checked several days after dose adjustment as it has long half life
when steady state is reached, frequent monitoring is not required
Everolimus:
not available in all reference labs
Bioavailability: the percentage of administered dose of drug that reach the target site for a defined time to make its therapeutic effect
MICHAEL Farag
3 years ago
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. For majority purposes, bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered
**Currie GM. Pharmacology, Part 2: Introduction to Pharmacokinetics. J Nucl Med Technol. 2018 Sep;46(3):221-230. [PubMed]
monitoring immunossupressive drugs
clinically by monitoring the side effects o the drug and we should educate the patient about them to consult the doctor once any of such symptoms and /or signs are manifested
drug level; and this depends on the time from transplantation. some drugs level only trough (before taking the dose) and others like cyclosporin has level after 2 hours from administration plus its trough level
we should counsel the patient about common drug-drug interaction and also some foods which can interfere with the immunosuppressive drug, in general, we should instruct the patient to avoid taking OTC or other medications without nephrologist consultation
You need to mention and explain the methods used for drug monitoring.
Mohamed Fouad
3 years ago
Bioavailability (F) 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.
*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-MTOR inhibitors:
Everolimus (Zortress) Oral bioavailability: 30%
*Effect of food in absorption: High-fat meal: ↓Cmax by 60%; ↓AUC by 16%,Should be taken at a consistent time each day in relation to meals
*Half-life in hours: 30 (19 to 41),Prolonged in hepatic impairment, excreted primarily via feces Sirolimus (Rapamune): Oral bioavailability: 18% (tablet),14% (oral solution)
*Effect of food in absorption: High-fat meal: ↑AUC by 23 to 35% Should be taken at a consistent time each day in relation to meals
Prograf 5 mg/ml concentrate for solution for infusion Oral Prograf therapy should commence at 0.10 – 0.20 mg/kg/day administered as two divided doses If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous therapy of 0.05 – 0.10 mg/kg/day should be initiated as a continuous 24-hour infusion SANDIMMUN Concentrate for Solution for Infusion 50mg/ml. The recommended dose of Sandimmun concentrate for solution for infusion is approximately one-third of the corresponding oral dose *Patients should be converted from intravenous to oral medication in both medications as soon as individual circumstances permit. Intravenous therapy should not be continued for more than 7 days Mycophenolate mofetil 500 mgpowder for concentrate for solution for infusion Mycophenolate mofetil for infusion is an alternative dosage form to Mycophenolate mofetil oral forms that may be administered for up to 14 days. The initial dose of Mycophenolate mofetil for infusion The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose).
fakhriya Alalawi
3 years ago
Immunosuppressants require therapeutic drug monitoring because of their narrow therapeutic index and significant inter-individual variability in blood concentrations. This variability can be because of factors like drug-nutrient interactions, drug-disease interactions, renal insufficiency, inflammation and infection, gender, age, polymorphism, and liver mass. Drug monitoring is widely practiced especially for cyclosporine, tacrolimus, sirolimus, everolimus, and mycophenolic acid.
Whole-blood trough concentrations of tacrolimus or cyclosporine are routinely monitored among kidney transplant recipients to achieve proper dosing and to avoid over-immunosuppression and drug toxicity. Since the CNI concentration should reflect a 12-hour trough or two-hour post-dose (C2) level, it should first be confirmed that the blood was drawn at the correct timing. Similarly, trough levels of everolimus or sirolimus for patients taking these agents should be measured.
Bioavailability is a term used to describe the percentage (or the fraction (F)) of an administered dose of a drug that reaches the systemic circulation. Different generic brands of the same transplant medications are available in the market. Most of the published reports on bioavailability focused on cyclosporine, followed by tacrolimus and MMF. Different Synthetic cyclosporines are currently approved for use in the United States except for 2 generic formulations of cyclosporine, Equoral ® and Gengraf.
Tsipotis et al, carried a Systematic Review and Meta-Analysis to examine the relative bioavailability of these medications through following the FDA guidance by comparing the rate (C max ) and extent (AUC (0–t) ) of absorption of generic formulations available worldwide relative to their brand counterparts, as well as he examined the efficacy and safety of generic cyclosporine formulations relative to the brand cyclosporine Neoral. He concluded that Generic formulations of cyclosporine, tacrolimus, and MMF met the FDA requirement for bioequivalence against their respective brand counterparts on the basis of the 90% CI of 0.80–1.25 for the T/R drug’s C max and AUC (0–t). However, substantial heterogeneity was observed. In subgroup analyses, the C max achieved by Cicloral ® relative to Neoral ® did not meet the FDA criteria for bioequivalence, raising concerns about its pharmacokinetic profile. In terms of efficacy and safety, generic cyclosporine formulations appeared non-inferior to Neoral in kidney transplant recipients; however, the results were deemed inconclusive due to the wide confidence limits around the effect estimates.
Moreover, a study of incident kidney transplant recipients found that first-year costs were significantly higher in patients receiving generic cyclosporine, compared to those treated with brand cyclosporine, due to dose escalation or addition of another immunosuppressant.
References:
1. Mohammadpour N, Elyasi S, Vahdati N, Mohammadpour AH, Shamsara J. A review on therapeutic drug monitoring of immunosuppressant drugs. Iran J Basic Med Sci. 2011 Nov;14(6):485-98. PMID: 23493821; PMCID: PMC3586862.
2. 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
Reem Younis
3 years ago
Many immunosuppressive drugs require measurement of their concentration with subsequent dosage adjustment. This is performed by therapeutic drug monitoring (TDM). The most common immunosuppressants require TDM because of the narrow therapeutic index and significant variability in blood concentration between individuals. Multiple factors contribute to interindividual variabilities like drug-nutrient interactions, drug disease interaction, renal insufficiency, inflammation, infection, age, and gender. In renal transplantation, both supratherapeutic and subtherapeutic drug concentrations can have a devasting result. In At subtherapeutic dose, the patient is at risk of allograft rejection while in the supratherapeutic dose patient may develop drug-specific side effects and infections. For Examples :
Cyclosporin
It is an acyclic peptide immunosuppressant used to prevent graft rejection and it improving long –term survival of a patient with a renal transplant. Earlier both blood and plasma were used to measure its concentration but now whole blood is used as a matrix for estimation for cyclosporine concentration.. several methods are used to assess cyclosporine, and each differs in specificity for the parent compound. High performance liquid chromatography(HPLC) is the most specific method and consider as the reference method. Its peak level is typically 2 hours (C2) s after dosing better than the trough level. Tacrolimus
It is an immunosuppressant that has emerged as a valuable therapeutic alternative to cyclosporin. It has a narrow therapeutic window. It is recommended that dosing be guided by routine TDM of whole blood trough concentration.
Mycophenolic Acid
It is an active immunosuppressant metabolite of the prodrug mycophenolate mofetil (MMF). It is effective in reducing the rate of acute rejection.it has large interindividual and intraindividual variability. Plasma is the preferred matrix for MPA measurement. It is mainly bound to albumin .so any change in albumin concentration can affect MPA concentration. Sirolimus
It is a new macrolide immunosuppressant derived from streptomyce hygroscpicus. It is poorly absorbed from GIT and oral bioavailability 15%. It is monitoring is necessary for successful patient management. Commonly whole blood has been used for trough levels. These drugs are also monitored by their clinical sides effect.
Bioavailability refers to the extent to which a substance or drug becomes completely available to its intended biological destination. More accurately, it is a measure of the rate and fraction of the initial dose of the drug that successfully reaches either; the site of action or the bodily fluid domain from which the drug,s intended targets have unimpeded access.1,2,3
References:
1.Currie GM. Pharmacology, Part 2: Introduction to Pharmacokinetics. J Nucl Med Technol. 2018 Sep;46(3):221-230. [PubMed]
2.Herkenne C, Alberti I, Naik A, Kalia YN, Mathy FX, Préat V, Guy RH. In vivo methods for the assessment of topical drug bioavailability. Pharm Res. 2008 Jan;25(1):87-103. [PMC free article] [PubMed]
3.Chow SC. Bioavailability and Bioequivalence in Drug Development. Wiley Interdiscip Rev Comput Stat. 2014;6(4):304-312. [PMC free article] [PubMed]
Mohamed Essmat
3 years ago
The idea of drug monitoring emerged aiming to reach better benefits from the immunosuppressive medications with less side effects .The fact that immunosuppression itself has many drawbacks being a double edged weapon necessitates close follow up .
There’s a thin line between over and under immunosuppression especially for those drugs with narrow therapeutic index , the success is to protect the kidney and the recipient as well from both rejection , infections (especially in the current COVID epidemic worldwide) and malignancies through therapeutic drug monitoring thus attaining the best level needed for immunosuppression with the least side effects .
Unexpected results from drug levels can occur due to unknown causes may be intraindividual causes ; idiosyncrasy may be a cause . Major events (rejection or infection) can occur even with targeted drug levels !! thus there’s no need to increase the risks more with failing to proper monitoring.
Timing of drug monitoring and frequency of doing so is according to guidelines , depending on the time of transplant , risk factors (desensitization and induction )levels before , changed doses , liver status , kidney status, other medications affecting the levels that may be introduced at any time after the transplant : antihypertensives or antibiotics or antifungals affecting the levels for example .
Tacrolimus has a narrow therapeutic index, trough level should be checked regularly according to guidelines
Cyclosporine trough level and peak level which is more important or more accurate as it correlates more to the AUC
MMF levels are monitored
Evirolimus and sirolimus levels are checked also according to guidelines
Drug bioavailability is defined as the extent at which the active metabolite of the drug enter the systemic circulation and reach the site of action.
Abbott KC, Kimmel PL, Dharnidharka V, et al. New-onset gout after kidney transplantation: incidence, risk factors and implications. Transplantation 2005; 80:1383. Barry D Kahan1, Paul Keown, Gary A Levy, Atholl Johnston, Therapeutic drug monitoring of immunosuppressant drugs in clinical practice. 2002 Mar;24(3):330-50; Osorio JM, Bravo J, Pérez A, et al. Magnesemia in renal transplant recipients: relation with immunosuppression and posttransplant diabetes. Transplant Proc 2010; 42:2910. Jennifer Le.Drug Bioavailability. MSD mannual professional version. Oct 2020
1- monitor therapeutic drug level
2- monitor for side effects and adverse reactions even within the therapeutic range.
Bioavailability= AUC for X route of administration / AUC for IV route of administration.
for oral medications, it is affected by GIT absorption, metabolism, hepatic metabolism, endothelial absorption, distribution, and utilisation.
Dear All What are the bioavailabilities of the following drugs and what are their clinical application?
Cyclosporine
Tacrolimus
Sirolimus
Mycophenolate Mofetil (MMF)
Azathioprine
Prednisolone
There is a present for the best answers (an original text of Transplant Immunology).
Last edited 3 years ago by Professor Ahmed Halawa
Shereen Yousef
3 years ago
Immunosuppressive drugs are used to reduce
the immune response in organ transplantation and autoimmune disease. In transplantation, the major classes of immunosuppressive drugs used today are: (1) glucocorticoids, (2) calcineurin inhibitors, (3) antiproliferative/antimetabolic agents, and (4) biologics (antibodies).
These drugs have a high degree of clinical success in treating conditions such as acute immune rejection of organ transplants and severe autoimmune diseases. But also they require lifelong use and nonspecifically suppress the entire immune system, exposing patients to considerably higher risks of adverse effects [1].
A narrow therapeutic index unique to each patient, as well as variable absorption, distribution, and elimination, are characteristics of these drugs. Therapeutic drug monitoring ensures that concentrations are not too high or too low, thereby reducing the risks of toxicity or rejection.
The therapeutic range (therapeutic index) is the ratio between the toxic dose and the therapeutic dose of a drug. The closer this ratio is to 1, the more difficult the drug is to use in clinical practice.
The therapeutic index for immunosuppressant drugs is very low . Clinical use of drugs with a narrow therapeutic index has led to the monitoring of drug concentrations in patients – therapeutic drug monitoring – in which the plasma concentration of a drug is measured and the dose adjusted to achieve a desired therapeutic drug concentration.
a therapeutic range is a range of drug concentrations within which the probability of the desired clinical response is relatively high and the probability of unacceptable toxicity is relatively low [2].
The aim of TDM is to optimize pharmacotherapy by maximizing therapeutic efficacy, while minimizing adverse events, in those instances where the blood concentration of the drug is a better predictor of the desired effect(s) than the dose.
Many factors contribute to the interindividual variability including drug-nutrients interactions, drug-disease interactions, renal insufficiency, inflammation and infection, gender, age, polymorphism and liver mass.
Therapeutic monitoring:
Cyclosporine (CsA)
With the original formulation of CsA, Sandimmune® C0 was the best practice, but during the conversion of patients from that formulation to the improved formulation, Neoral® the 2 h post-dose concentration has been advocated as a single concentration monitoring alternative to C0 [3].
The area under the concentration-time curve for CsA over a 12-hour drug administration interval (AUC0-12h) was a more precise predictor of graft loss and incidence of acute rejection than other parameters, including the C0. Since then, subsequent studies on the pharmacokinetics of CsA in renal transplant patients have identified that intrapatient variability in AUC values over time was directly correlated with the risk of chronic rejection [3].
Tacrolimus (TRL)
The therapeutic range for TRL used by most transplantation centers is 5–20 ng/mL in blood.
TRL whole-blood through concentrations have been found to correlate well with the area under the concentration-time curve measurements in liver, kidney and bone marrow transplant recipients (r= 0.91-0.99). Thus, through concentrations are good index of overall drug exposure, and are currently used for routine monitoring as part of patient care posttransplantation [4].
Therapeutic ranges of TRL after kidney transplantation are reported as a range for various times after transplant: 0-1 month, 15-20 μg/L; 1-3 months, 10-15 μg/L; and more than 3 months, 5-12 μg/L [95]. TRL blood concentrations are monitored 3 to 7 days a week for the first 2 weeks, at least three times for the following 2 weeks, and whenever the patient comes for an outpatient visit thereafter [5].
Mycophenolic acid (MPA)
MPA TDM is currently only used in a few transplant centers on a routine basis, whereas a few others only checked MPA exposure in case of unexpected acute rejection or adverse event or drug interaction. Most of the centers never measure MPA.
Sirolimus (SRL)
Because of the long half-life and extensive tissue distribution of the drug, steady-state concentrations are not reached before day 6 after initiation of therapy or after a dosage change. Thus, daily concentration monitoring is not necessary; the first SRL measurements should not be obtained before day 4 after inception of, or change in therapy. Thereafter, recommend monitoring Cmin,ss weekly for the first month and bi-weekly for the next month, targeting a 5 to 15 μg/L range if CsA is being used concomitantly .
Everolimus (EVL)
EVL is a drug with a narrow therapeutic index.
The recommended therapeutic range for EVL is a trough concentration of 3 to 8 ng/mL.
Reference
1 Krensky AM, Vincenti F, Bennett WM. Immunosuppressants, Tolerogens, and Immunostimulants. In: Brunton L. (ed) Goodman and Gilman’s The Pharmacological Basis of Therapeutics 11th ed. McGraw-Hill Co. New York, NY. 2006.
2 Evans W. General Principles of Clinical Pharmacokinetics. In: Burton ME., Shaw LM., Schentag JJ., Evans WE. (ed) Applied Pharmacokinetics and Pharmacodynamics. Principles of Therapeutic Drug Monitoring. USA: Williams and Wilkins; 2006.
3 Johnston A., Holt DW. Cyclosporine. In: Burton ME., Shaw LM., Schentag JJ., Evans WE. (ed) Applied Pharmacokinetics and Pharmacodynamics. Principles of Therapeutic Drug Monitoring. USA: Williams and Wilkins; 2006.
4Staatz C, Taylor P, Tett S. Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation. Nephrology Dialysis and Transplantation 2001;16(9):1905-9.
5 Scott LJ, McKeage K, Keam SJ, Plosker GL. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003.
6
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
Bioavailability is that fraction of the administered drug which reaches systemic circulation and reaches site of action.
as we know most of ktrs patients uses triple immunosuppresion in form low dose predinsolone, with antimetabilite either (azathiprine or mmf, and cnis either (cyclosporine or tacrolimus).also mTOR inhibitors like sirolimus and evorlimus are used.
The therapeutic drug level monitoring (TDM) is important because an optimal drug level will help in preventing rejections and avoiding toxicity of the drug causing side-effects.
some drugs like cnis and sirolimus should be mointored according to how far is the pt from tranplantion.
for example
a-Tacrolimus: Trough whole blood levels (sample is taken just before the dose intake, 12 hours post last dose; 24 hours after last dose, if using long acting tacrolimus) correlates well with AUC, especially in first few months post transplant.
b-Cyclosporine: Trough plasma (C0) levels (sample is taken just before the dose intake, 12 hours post last dose) as well as blood levels taken 2 hours after dose (C2 levels) correlate well with AUC.
c-sirolimus and Everolimus: Trough whole blood levels (sample is taken just before the dose intake, 12 hours post last dose)
Last edited 3 years ago by MOHAMMED GAFAR medi913911@gmail.com
Rania Mahmoud - Suspended
3 years ago
-The immunosuppressive medicines’ pharmacokinetics are complicated and variable. –Therapeutic medication monitoring is critical in assisting clinicians in keeping immunosuppressive drug levels in the blood and plasma within therapeutic ranges. Excessive variation in concentrations outside of the narrow therapeutic ranges can have significant clinical consequences. Therapeutic medication monitoring ensures that concentrations are not excessively high or low, lowering the risk of toxicity or rejection.
-cyclosporine, tacrolimus, mycophenolic acid, sirolimus, everolimus, azathioprine, daclizumab and basiliximab, alemtuzumab, and glucocorticoids are some of the immunosuppressive medications.
-Biovalidity is the degree and rate at which the active component (drug or metabolite) enters systemic circulation
-It depends on 3 factors :pharmaceutical factors, patient related factors, route of administration
-Chemical equivalence:
2 or more formulations have the same designated chemical substance in the same amount as an active ingredient.
-Pharmaceutics equivalence:
2 or more formulations are the same in strength,content uniformity, purity,quality , disintegration and dissolution characteristics
Reference
–Piedras, A.L.R., De la O Arciniega, M. and Vázquez, J.R., 2013. Clinical pharmacology and therapeutic drug monitoring of immunosuppressive agents. In Current Issues and Future Direction in Kidney Transplantation. IntechOpen.
Mujtaba Zuhair
3 years ago
The immunosuppressive drugs is monitored to allow the use of lowest dose to prevent rejection and at the same time the side effects to be at minimum.
some drugs needs drug level monitoring , while others need monitoring of adverse effects only.
Cyclosporine : There is some debate about the use of C0 or C2 in the monitoring of drug level . C2 correlate better with AUC , and some studies corelate it with less acute rejection in first months after transplantation. C0 is more convenient to use , and there is no study to prove that C2 is better than C0. So it a good idea to use C2 level in the first 3 months after transplantation and to use C0 after that.
Tacrolimus : Drug trough level is used 10-15 ng/dl in the first 6 months, and 5-10 ng/dl after that.
MMF: drug trough level is not consistent with outcome , since this drug had 2 peaks , and AUC is better for monitoring , but it is time consuming and difficult to calculate. in practice no need for drug level monitoring, just monitor for adverse effects.
Sirolimus : Had long halve life , so we need to monitor it’s trough level after steady state had been reached.
Everolimus: drug trough level 3-8 ng/dl
Azathioprine : monitore for side effects only
Bioavailability: is the amount of the drug that reach systemic circulation after it had been ingested by the patient.
Ala Ali
Admin
3 years ago
What are the types of Lab tools that can be used for TDM? What is the most useful? Why you should know the apparatus used for TDM of CNI?
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%
AMAL Anan
3 years ago
Bioavailability is defined as the extent of a substance or drug becomes completely available to its intended biological destination. Really the 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 body fluid from which the drug’s intended targets have unimpeded access. Due to purposes a bioavailability is related to the fraction of the active form of a drug that reaches systemic circulation unaltered. This definition achieved 100% of the active drug that enters systemic circulation will successfully reach the target site .Although, it should be appreciated that this definition is not inclusive of drugs that do not require access to systemic circulation for function The bioavailability of these drugs is measured by different parameters discussed elsewhere.
>>> Therapeutic drug monitoring :
plays a key role in helping clinicians maintain blood and plasma levels of immunosuppressive drugs within their respective therapeutic ranges.
***Therapeutic drug monitoring (TDM) of immunosuppressive drugs is becoming an increasingly complex matter as the number of compounds and their respective combinations are continuously expanding. Unfortunately, in clinical practice, monitoring predose trough blood concentrations is often not sufficient for guiding optimal long-term dosing of these drugs. The excellent short-term results obtained nowadays in renal transplantation confer a misleading feeling of safety despite the fact that long-term results have not substantially improved, really there’s a point where longer graft survival could counteract the increasing need for transplant organs and less toxicity and side-effects could ameliorate patient survival.
*** Calcineurin inhibitors >>>
Tacrolimus
We must pay attention that predose trough blood tacrolimus concentrations (C0) do not accurately reflect total drug exposure as measured by the 12-h dose interval area under the concentration curve (AUC0−12 h), both in renal and other solid organ transplantation . Especially when C0 is evaluated for its clinically relevant predictive accuracy, by calculating both the prediction error and bias , the usefulness of tacrolimus trough concentrations is questionable. Other clinical studies that repeatedly showed an excellent correlation between tacrolimus C0 and AUC0−12h were often in nonrenal transplantation and failed to examine predictive performance of C0 as suggested .It seems not surprising that every single blood concentration sampling time point is prone to a substantial bias, caused by practical factors such as the exact method and timing of sampling.
Today, few prospective studies can actually demonstrate a clear relationship between tacrolimus exposure which measured as predose trough concentration and clinical efficacy and toxicity.
In additional ,another difficulty with defining useful tacrolimus target concentration ranges is the time dependency of the latter and the changing influence of clinical and biological factors. It is obvious that early after grafting higher immunosuppressive drug concentrations are required in order to prevent rejection while later on during follow-up, chronic drug toxicity becomes an important issue .As a result, early after transplantation, serious side-effects are caused by overimmunosuppression (e.g. infections, PTDM, neurotoxicity).
Cyclosporine :
It’s shown that Mahalati et al. was the first to show prospectively that abbreviated 4-h AUC concentration profiles were superior to C0 with respect to predicting clinical efficacy (prevention of acute rejection) and nephrotoxicity . Abundant other limited sampling strategies for cyclosporin were proposed of which several adequately predicted the full dose-interval AUC and were recently summarized by David and Johnston . The conclusion of the latter review of 38 studies was clear, there is no ‘best’ algorithm for estimating cyclosporin AUC from sparse data.
Mainly for reasons of practical simplicity a new single cyclosporin concentration sampling point was derived form Mahalati’s AUC0−4 data and gave rise to the new concept of C2 monitoring. Although Mahalati et al. found C3 as best predictor of the 12-h dose-interval AUC that correlated with acute rejection and nephrotoxicity during the first week after transplantation , C2 better reflected the time point of maximal pharmacodynamic effect of cyclosporin measured as percentage inhibition of calcineurin and suppression of interleukin-2 release from T cells . The cyclosporin blood concentration 2h post-dosing was relatively easy and accurate to determine with different assays and was the best predictor for the 4-h cyclosporin AUC in subsequent studies .There are a lot of studies in kidney and liver transplantation validated the use of cyclosporin C2 monitoring for prevention of acute rejection and to a lesser extent for reducing calcineurin-inhibitor-induced nephrotoxicity .
It was found that A C2 level ≥1700ng/ml on day 3 post-transplantation had a 92% negative predictive value for acute kidney rejection in the first 6months for recipients without delayed graft function . This minimal C2 threshold was subsequently refined to 1500 ng/ml (on day 7) by the findings of two other studies in renal recipients, one protocol with and the other without induction with monoclonal antibodies against the interleukin-2 receptor .
***Mycophenolate mofetil>>>
The main target involving TDM for MPA are distinct from that of calcineurin inhibitors. It is clear in renal transplantation that predose trough plasma concentrations of MPA do not predict total drug exposure measured as 12-h AUC and that abbreviated 2-h AUC profiles, usually obtained by three concentration sampling points (C0, C30 or C40 and C2), are accurate in predicting total exposure . The free (pharmacologically active) fraction of the drug is determined by allograft dysfunction through alterations in albumin binding and secondary to increased levels of the glucuronide MPA metabolites that are excreted by the kidney , the inactive MPAG-glucuronide and the pharmacologically active Acylglucuronide . The fact that the latter is also implicated in the occurrence of clinically relevant side-effects like diarrhoea and anaemia , further complicates the situation. Finally, the pharmacokinetics of MPA are characterized by a specific postoperative evolution that is mainly determined by the daily dose of the drug and the concomitant calcineurin
inhibitor.
For anaemia we must also consider a relationship with MPA exposure (AUC), like others as well as for leukopenia . Other MMF-associated adverse events like gastrointestinal side-effects were poorly associated with MPA exposure in our study as shown by others .
In order to address at least some of the problems of applying abbreviated MPA AUC measurements in clinical practice, a large international multicentre study in renal transplantation has recently commenced, examining the clinical relevance of concentration-controlled MMF dose adjustments based on abbreviated (2-h) target AUC profiles versus fixed dose treatment. Whether TDM of MMF is advantageous in terms of both efficacy (prevention of acute rejection) and toxicity will be assessed in this trial.
***mTOR inhibitors>>>
There’s no doubts about that TDM is necessary for clinical application of sirolimus in solid organ transplantation .Few studies have demonstrated that, similar to calcineurin inhibitors, mTOR inhibitors are characterized by a narrow therapeutic window, highly variable absorption and large intra- and interindividual variability in pharmacokinetic behaviour . However when sirolimus is used in a low fixed dose of 2mg/day in combination with a full dose cyclosporin (separated by 4h), systematic concentration monitoring can usually be omitted .The latter implies a minimal obtained blood sirolimus trough concentration of 5ng/ml as this shown a clinical threshold differentiating for acute rejection, at least in combination with cyclosporin . Whether long-term association of sirolimus and tacrolimus does not cause alterations of both drug’s blood concentration, remains unclear . Reports showing an effect of a standard dose tacrolimus on maintenance low dose sirolimus imply an interaction .Interestingly, significant decreases in tacrolimus exposure were observed early after transplantation in another report using low doses of sirolimus .
The upper limit of sirolimus exposure, discriminating the onset of adverse events, was determined around 15ng/ml in several studies combining the former with cyclosporin . Especially for thrombocytopenia and hypertriglyceridaemia an exposure–response relationship could be defined. Using receiver operating characteristic curves, an inflection point for thrombocytopenia of 14ng/ml, hypertriglyceridaemia of 11ng/ml and hypercholesterolaemia of 13ng/ml could be determined . With everolimus, a similar exposure–response relationship could be discerned for thrombocytopenia and to a lesser extent for hypertriglyceridaemia and hypercholesterolaemia.
The above data permit us to prudently outline a therapeutic window for sirolimus between 5 and 15g/ml in combination with cyclosporin. However, when cyclosporin is eliminated from this combination higher target levels between 12 and 20ng/ml are advised based on the results of a large multicentre trial examining the feasibility of early calcineurin-inhibitor elimination .As sirolimus seems to induce a different type of allograft nephrotoxicity, distinct from that of calcineurin inhibitors.
### Finally >>>>
~Therapeutic drug monitoring remains the cornerstone of today’s concentration-controlled management of immunosuppressive therapy in renal transplantation. Despite the spectacular evolution in pharmacodynamic research, the progressive unravelling of the individual pharmacogenomic profile and the useful application of drug probes in order to identify drug metabolism, clinicians still have to rely on classic TDM for daily patient care. In recent years it has become clear that abbreviated AUC concentrations are stronger and more reliable predictors of concentration–exposure and exposure–response relationships for the majority of currently used immunosuppressive drugs. Comparative prospective clinical trials are necessary in order to objectively weight the advantages of abbreviated AUC monitoring against classic predose trough concentrations, in terms of cost-effectiveness, feasibility and clinical relevance with regard to long-term patient morbidity and mortality and graft survival. At the same time, it is a challenging task to further refine the therapeutic window for the individual drugs and more importantly for the increasing number of different drug combinations. In order to do so, large prospective observational pharmacokinetic studies are mandatory, carefully examining the relationship between drug exposure and clearly defined efficacy and toxicity endpoints. This relationship has to be studied in a long-term, time-dependent manner in order to recognize important changes in drug (and drug metabolite) pharmacokinetics and identify crucial time points after successful transplantation for optimal use of AUC monitoring.
Routine follow up is recommended to be done by transplant nephrologist in first year then by general nephrologist thereafter since risk of complications decrease after first transplant year.
Routine follow up visits may be done as follow :
⦁ Twice weekly in first month
⦁ Weekly for 1 m
⦁ Every 2 weeks for 1m
Then after first 3 months, monitoring is recommended every 3 m
a- Tacrolimus T0 (12 h for immediate release and 24 hrs for extended release formulation)
⦁ If rATG is used for induction it is recommended to keep T0 at 7-10 ng/ml in the first month then 3-7 ng/ml thereafter.
⦁ If rATG is not used for induction it is recommended to keep T0 at 8-10 ng/ml in the
b- Cyclosporine C0 (12-hour )
⦁ 200- 300 ng/ml in first 3 months, and 50-150 thereafter
Drug bioavailability :
⦁ Explain the relationship between the dose of drug given and the its level in blood.
⦁ Tacrolimus level may differ in the same patient taking the same dose (intra – patient variability) as food decrease absorption of tacrolimus by 30%.
⦁ Tacrolimus level may differ between patients taking the same dose (inter – patient variability) depending on the activity of cytochrome B450 which differ between renal transplant recipients.
⦁ Patients with higher activity of cytochrome B450 are more prone to have lower level of tacrolimus in blood, and tend to use higher doses of tacrolimus to achieve therapeutic drug level, these patients have higher incidence of rejection and graft loss.
⦁ If the drug level divided by the dose of tacrolimus used was < 1 that mean this patient is fast metabolizer, and need higher doses of tacrolimus.
⦁ Moreover, we have to beer in mind that elderly patients have lesser activity of cytochrome P450 when compared to young and may need lower doses of tacrolimus than young.
II- Monitoring of toxicity of immunosuppressive drugs :
1- Cosmetic problems such as gingival hyperplasia, hirsutism (cyclosporine), alopecia (tacrolimus),
2- HTN, PTDM, hyperlipidemia (2)
⦁ Related to the use of CNI, corticosteroids
⦁ So it is recommended to check for blood glucose with each follow up visit and screen for HBA1c, lipid profile every 3 m for 1 year starting from 3 m post transplant then annually
3- Neurological abnormalities such as tremors (tacrolimus), posterior reversible leukoencephalopathy (tacrolimus, MMF)
4- Infection: all immunosuppressive increase risk of infections, which increase risk of death (3). So it is recommended to screen for the following :
⦁ BK virus using urine and/ or blood test every month for 6 months then /3 m for 2 ys post transplantation.
⦁ CMV by PCR in patients not receiving prophylaxis to be done weekly in first 3 month post transplant, and in patients receiving prophylaxis every 3 m for 1y (R+/D+) or for 2 ys (R-/D+)
5-Malignancy
⦁ Renal transplant recipient have 3 fold increase in risk of malignancy when copared to general population, espicially skin, lip cancers, PTLD, kaposi sarcoma, anogenital cancer and RCC (4)
⦁ Screening of cancer is as general population except for skin cancer which should be done by the patietn every month and by expert dermatologist every year.
⦁ May be due to multible causes but when talking in relation to immunosupressive drugs the most common cause of renal dysfunction are overdose of CNI (drug toxicity, viral infection, interstitial nephritis associated with PTLD), or subtherabiotic dose (rejection) or CAN, or may be due to TMA related to CNI
⦁ Also CNI can cause hyperkalemia, hypomagnesimia (5)
⦁ So it is recommended to do creatinine, electrolytes, urine analysis with each follow up visit, and protein- creatinie ratio every 3 m till 1 year post transplant then every 6-12 mounth therafter
⦁ Renal biopsy is indicated if there is allograft dysfunction
7- Hyperuricemia is common with CNI as they decrease excretion of UA In urine. 96)
8- GIT and hepatobiliary side effects especially diarrhea with mycophenolate mophetile can be improved when switching to enteric coated formulation and hepatitis with azathioprine
9- Hematologic side effects including
⦁ Anemia (CNI, azathioprine, MMF)
⦁ Leukopenia (azathioprine, MMF) (7)
⦁ TMA (CNI)
⦁ So it is recommended to monitor CBC with each follow up visit
10- Bone disease
⦁ Osteoporosis due to glucocorticoids, CNIs, persistent hyperparathyroidism may play a rule
⦁ So it is recommended to measure serum ca, p with each fu visit, fu vit D and PTH every 6 m, DEXA scan 3 m post transplant and if there is risk of fracture repeat it every 6-12 m.
III- Monitoring for drug-drug interactions
1- 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.
2- 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.
3- Statin may increase the level of tacrolimus, and increase muscle toxicity with cyclosporine
4- Cyclosporine decrease level of MMF.
5- Allopurinol and febuxistat should not be used with azathioprine.
6- PPI decrease effect of MMF but not EC-MPS.
REFERANCES
1-Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3:S1.
2-Kasiske BL, Guijarro C, Massy ZA, et al. Cardiovascular disease after renal transplantation. J Am Soc Nephrol 1996; 7:158.
3- The AST Infectious Disease Community of Practice, Amercian Society of Transplantation, Infectious Disease Guidelines for Transplantation. Am J Transpl 2009; 9 (Suppl 4):S1.
4- Vajdic CM, McDonald SP, McCredie MR, et al. Cancer incidence before and after kidney transplantation. JAMA 2006; 296:2823.
5- Osorio JM, Bravo J, Pérez A, et al. Magnesemia in renal transplant recipients: relation with immunosuppression and posttransplant diabetes. Transplant Proc 2010; 42:2910.
6- Abbott KC, Kimmel PL, Dharnidharka V, et al. New-onset gout after kidney transplantation: incidence, risk factors and implications. Transplantation 2005; 80:1383.
7- Hartmann EL, Gatesman M, Roskopf-Somerville J, et al. Management of leukopenia in kidney and pancreas transplant recipients. Clin Transplant 2008; 22:822.
If we give the same dose of a drug orally and intravenously, the drug level when given intravenously will be higher since it will reach the circulation directly without being affected by gastrointestinal absorption and hepatic first pass.
When the drug is administered IV its bioavalibity is 100%. However when administered by oral route, its bioavalibity is generally lower than IV route due to intestinal absorption and first-pass metabolism.
Weam Elnazer
3 years ago
1-Due to a narrow therapeutic index and large interpatient pharmacokinetic variability, TDM is routinely performed for individualization of the Tac dose to maintain drug efficacy and minimize the consequences of under- and overexposure.
Unfortunately, the evidence for the optimal Tac C0 is more limited than one would expect of a drug so extensively pre-scribed and studied.
Based on the current literature, there is little support to promote a specific therapeutic window. Besides this, the relationship between Tac concentration and either acute rejection or toxicity remains controversial.
Acute cellular rejection episodes occur when the Tac concentration is within the target concentration range and patients having supra-therapeutic exposure sometimes do not suffer from side effects.
This suggests that Tac whole-blood predose concentrations do not always correlate with its pharmacological effect and indicate that novel matrix or monitoring strategies are needed to better predict and monitor the effect of Tac treatment.
Novel options include the measurement of Tac concentrations within the lymphocyte and the unbound concentration. Both options are technically demanding but seem feasible with the recent availability of sophisticated analytical methods.
The intracellular Tac concentration is the most extensively studied option of the two. An association between the Tac concentration and acute rejection has been demonstrated
As Tac is mainly metabolized by CYP3A5, and as it is known that CYP3A5 expressers require a two-fold higher dose to reach the same exposure compared with non-expressers, it seems reasonable to implement preemptive pharmacogenetic testing.
However, two RCTs failed to demonstrate a decreased risk of acute rejection or any other clinical benefit of basing the Tac starting dose on an individual’sCYP3A5 genotype. More sophisticated dosing strategies are needed.
Sirolimus: clinically useful target concentration window (C0: 10–12 ng/ml in the first 6 months post-transplantation and 5–10 ng/ml thereafter), Downloaded by [Erasmus University] at 06:18 15 December 20 2-Bioavailability is that fraction of the administered drug which reaches systemic circulation. It can be calculated by diving the AUC of the oral drug by AUC of intravenous drug and multiplying by 100
Louise M. Andrews, Yi Li, Brenda C. M. De Winter, Yun-Ying Shi, Carla C.Baan, Teun Van Gelder & Dennis A. Hesselink (2017) Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients, Expert Opinion on DrugMetabolism & Toxicology, 13:12, 1225-1236, DOI: 10.1080/17425255.2017.1395413
Flechner SM, Goldfarb D, Modlin C, et al. Kidney transplantation without calcineurin-inhibitor drugs: a prospective, randomised trial of sirolimus versus cyclosporine. Transplantation 2002; 74: 1070. Louise M. Andrews, Yi Li, Brenda C. M. De Winter, Yun-Ying Shi, Carla C. Baan, Teun Van Gelder & Dennis A. Hesselink (2017) Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients, Expert Opinion on Drug Metabolism & Toxicology, 13:12, 1225-1236, DOI: 10.1080/17425255.2017.1395413
Mahmoud Hamada
3 years ago
As some immunosuppressive drugs has narrow therapeutic window e.g Tacrolimus and cyclosporine, their blood level should be regularly detected to avoid either toxicity or graft rejection.
The protocol of monitoring depend on the point of time since transplantation , with close and more frequent monitoring is used during early days post transplantation, and regular monthly then quarterly monitoring later on.
The way of measuring the drug level is either trough level (just before the dose) or C2 (2 hours post dose) with the latter more effective as per some reports(1)
Levy G, Thervet E, Lake J, Uchida K; Consensus on Neoral C(2): Expert Review in Transplantation (CONCERT) Group. Patient management by Neoral C(2) monitoring: an international consensus statement. Transplantation. 2002 May 15;73(9 Suppl):S12-8. doi: 10.1097/00007890-200205151-00003. PMID: 12023608.
Wael Hassan
3 years ago
Bioavailability of the drug mean the ability of the drug or its active metabolit to reach blood stream (systemic circulation)
Monitoring of immunosuppressant drugs with drug trogh level (not exceed it) and kept in its therapeutic level according to time of the transplanted graft
Fatima AlTaher
3 years ago
Monitoring of immunosuppressive drugs after kidney transplantation is critical to achieve therapeutic level and avoid drug toxicity .Itis involves both clinical and therapeutic monitoring 1- ATG : clinical monitoring for signs of cytokine release or allergic reaction As well as monitoring level of CD3 to adjust the dose (not universally agreed). 2- Tacrolimus : through monitoring 12 h through level in serum 3- Cyclosporine through C2 ( serum drug level 2 h after the dose) (1) Drug bioavailability : define as a measurement of the rate and fraction of the initial drug dose that succeed to reach site of drug action or the body compartment where the drug can be monitored. (2) 1- Holt, D. W. (2002). Therapeutic drug monitoring of immunosuppressive drugs in kidney transplantation. Current opinion in nephrology and hypertension, 11(6), 657-663. 2- Price, G., & Patel, D. A. (2020). Drug Bioavailability.
Mohamad Habli
3 years ago
How do you monitor the immunosuppression drugs?
Immunosuppressive therapy in renal transplant patients is the cornerstone to avoid rejection. Immunosuppression drugs have narrow therapeutic levels above which toxicity may occur, with a risk of rejection if dose is reduced or levels are not in the therapeutic targets.
Maintenance immunosuppressive therapy included CNI, antimetabolite, steroids and mTORi.
For calcineurin inhibitors, patients treated with tacrolimus, we monitor whole-blood 12- and 24-hour trough (C0) concentrations for the immediate-release and extended-release preparations, respectively. C0 target levels adepends on the initial induction therapy:
In patients who receive antilymphocyte-depleting:
-7 to 10 ng/mL for the first month after transplantation
-3 to 7 ng/mL for subsequent months
In patients who do not receive antilymphocyte-depleting agents for induction therapy:
-8 to 10 ng/mL for months 1 to 3 after transplantation
-3 to 7 ng/mL for subsequent months
In most patients treated with cyclosporine, we monitor whole-blood 12-hour trough (C0) concentrations. With this approach, our C0 target levels are the following:
-200 to 300 ng/mL in months 1 to 3 after transplantation
-50 to 150 ng/mL for subsequent months
Patients on CNI may develop toxicity even in the narrow therapeutic level, so side effects and toxicity should be monitored. If patients are unable to tolerate these agents due to toxicity or other adverse effects, alternative immunosuppression drugs should be considered involving the use of mTOR inhibitors or belatacept.
For mTORi, in particular Everolimus, the recommended therapeutic range is a trough concentration of 3 to 8 ng/mL. For Sirolimus thetherapeutic target is 5 to 15 μg/L.
For antimetabolic agents, we do not obtain target or trough levels now, since they are not routinely available, reliable, or associated with efficacy or toxicity.
For the Dosing of glucocorticoids, there is no consensus on the optimal dose or maintenance schedule of glucocorticoids following kidney transplantation but the target is to reach the least effective dose and in some protocols to stop steroids. We don’t measure steroids level but we monitor side effects of the immunosuppressive therapy including steroids.
What is meant by “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.
Ibrahim Omar
3 years ago
bioavailability is a term in pharmacology, meaning the percentage of the amount of a specific drug reaching the blood circulation after a certain time of intake of that drug.
Ibrahim Omar
3 years ago
immunosuppressive drugs can be monitored by :
1- clinical signs of side effects and toxicity, e.g tremors for CNI, GIT symptoms as diarrhea for MMF, cushinoid features of steroids,…. etc
2- serum levels of drugs as trough levels of CNI.
3- histopathology feaures of toxicity as CNI toxicity.
Ahmed Fouad Omar
3 years ago
Immunosuppressive management is an art in managing renal transplant patients. It is a balance between providing adequate immunosuppression to achieve desired clinical effects to reduce the risk of rejection without exposing the patient to their toxic side effects .
Immunosuppressive medications has narrow therapeutic window and both intra and inter pharmacokinetic variability. Accordingly, therapeutic drug monitoring (TDM) for these agents is essential by measurement of drugs and/or their breakdown products (metabolites) at timed intervals to maintain a relatively constant concentration of the medication in the blood and to limit sub and supra therapeutic drug exposure and concurrent risk for graft rejection and toxicity.
Examples of monitored drugs:
Cyclosporine: monitoring of C2 after the dosing is more sensitive predictor of the outcome than trough C0 monitoring. However, C0 levels are more widely used
Tacrolimus: C0 is used in clinical practice, 12 hr trough concentration for immediate release preparation and 24 hr trough concentration for extended release preparation. however, the relation between C0 and AUC(area under the curve varied between clinical trials)
Mycophenolic acid: concentration is not correlated with drug exposure or outcome
Sirolimus and Everolimus: Trough whole blood levels ,the sample is taken just before the dose intake, 12 hours post last dose.
Bioavailability is defined as the ability of a drug to be absorbed at utilized by the body(enter the circulation and reaches the site of its action)
· Jennifer Le , Drug Bioavailability .MSD Manual professional version .Oct 2020
· Up to date. cited on 7th Nov. 2021
· Handbook of Kidney Transplantation, Danovitch. 6th edition
Ban Mezher
3 years ago
Close monitoring of CNI is pivotal in the management of renal transplant recipients because the response & metabolism differs from patient to another. Also there is a close relation between blood level of drug & organ rejection or toxicity.
During monitoring of Cyclosporine ( sandimmun) trough level used ( C min) but in monitoring of Neoral usually use peak level (C2) because it correlate better with drug exposure than trough level.
Tacrolimus level usually monitoring by measuring trough level ( immediately before next dose).
Sirolimus has long half life, so drug level monitoring done after several days of dose adjustments & once the drug level became stable, frequent monitoring not required.
Bioavailability: referred to both the amount & the rate of drug absorption. The amount of absorbed drug referred to the portion of the drug that reach to blood stream in active form.Bioavailability of oral drugs affected by physical & chemical factors which in turn affect the absorption. These factors include gastrointestinal mucous membrane, GI transient time, & first bypass &/ or excretion by bowel or liver.
References:
Handbook of Kidney Transplantation, Danovitch. 6th edition.
Srinivas T., Meier-Kriesche H., and Kaplan B. Pharmacokinetic Principles of Immunosuppressive Drugs. American Journal of Transplantation, 2005;5:207-217.
Assafi Mohammed
3 years ago
Monitoring of the Immunosuppression drugs:
The goal is to attain an optimal balance between therapeutic efficacy and the probability of adverse effects.
The emergence of Therapeutic Drug monitoring (TDM) offered an opportunity to minimize the pharmacokinetic component of variability by managing drug therapy using concentrations in the body instead of dosages.
Interindividual variability in drug concentrations creates the need for TDM.
Factors that cause interindividual variability include:Drug-nutrient interactions ,Drug-disease interactions, Gender, Infection, Inflammation, Liver mass & Renal insufficiency.
Supratherapeutic drug concentrations, put the patient at-risk of over-immunosuppression which leads to infection.
Subtherapeutic drug concentrations can cause the recipient’s body to reject an allograft.
Microsampling is Important in Therapeutic Drug Monitoring:
Just a few decades ago, conventional techniques such as Venous Blood Sampling were used to obtain plasma or serum samples for TDM. With the invention of dried blood sampling, clinicians can enjoy a simple and convenient sampling method.
DBS(dried blood spot) sampling involves taking blood samples with a small finger prick using an automatic lancet. With the right setup, the right equipment, and adequate training, this can allow remote patient monitoring.
Immunosuppression that need TDM include:
Cyclosporine: Cyclosporine has proven to be effective in improving long-term survival of solid-organ transplant patients. TDM of cyclosporine is essential because of:
Drug-induced nephrotoxicity
Inter/intra-patient variability of drug absorption
Narrow therapeutic window
Mycophenolic Acid (MPA) – MPA is effective at reducing acute organ rejection in heart, kidney, or renal transplant patients. MPA has also been used along with sirolimus and tacrolimus. Additionally, the drug has recently gained popularity as the primary component in long-term immunosuppressant routines.
However, TDM is essential when using MPA on post-transplant patients because of the interaction of drugs and its effect on kidney functions. Researchers should also consider inter-patient pharmacokinetic variability for MPA and the relationship between MPA and pharmacokinetic parameters.
Tacrolimus – has a narrow therapeutic window. This drug exhibits large intra-/inter-individual inconsistency during pharmacokinetics assessment in liver and kidney transplant patients. The patients display significant associations between high concentrations with nephrotoxicity and low tacrolimus concentrations with rejection. That makes routine TDM of whole blood concentration critical.
Bioavailability:
Definition:Bioavailability refers to the extent a substance or drug becomes completely available to its intended biological destination(s).
Simply :The degree to which or rate at which a drug or other substance is absorbed or becomes available at the site of physiological activity after administration.
Excellent Yes, “the degree to which or the rate at which a drug or other substance is absorbed or becomes available at the site of physiological activity after administration”.
Dalia Ali
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. Differences in bioavailability among formulations of a given drug can have clinical significance; thus, knowing whether drug formulations are equivalent is essential.(1)
Immune suppressive drugs monitoring
1-drugs doses
2-patient compliance
3-drugs interaction like with other immune suppression drugs ,antibiotics ,anticonvulsant
4-side effects of drugs (history and examination)
5-serum drug level
6-in calcinurine inhibitors need renal function test and s.electrolytes
7-in MMF,AZA need CBP
8-in M-TOR inhibitors need GUE for proteinurea
Reference
By Jennifer Le, PharmD, MAS, BCPS-ID, FIDSA, FCCP, FCSHP, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego
Last full review/revision Oct 2020| Content last modified Oct 2020
Huda Al-Taee
3 years ago
Bioavailability: the proportion of a drug administered by any non vascular route that gain access to the systemic circulation.1
we monitor the immunosuppressive drugs through therapeutic drug level monitoring.
for CNI:
1.Tacrolimus: 12 hr trough concentration ( C0) for immediate release preparation & 24 hr trough concentration for extended release preparation.
target levels for those who receive ATG for induction:
7-10 ng/ml for the first month after transplantation
3-7 ng/ml for subsequent months
target for those who do not receive ATG for induction:
8-10 ng/ml for 1-3 months post transplant
3-7 ng/ml for subsequent months.
2.cyclosporine:
in most patients monitoring of C0 level has been done
target levels:
200-300 ng/ml in 1-3 months post transplantation
50-150 ng/ml for subsequent months
poor correlation between clinical outcome and drug exposure noticed by measuring C0 level, thus in some patients( poor absorption of cyclosporine), monitoring of C2 level is required( 2 hr.s post drug exposure).
target levels:
800-1000 ng/ml in the 1-3 months post transplantation
400-600 ng/ml in the subsequent months
antimetabolites:
Azathioprine, MMF : no tests done since they are not routinely available, reliable or associated with toxicity.
mTOR inhibitors
sirolimus if used with cyclosporine and prednisolone trough level of 5-15 ng/ml associated with protection from rejection
if used with azathioprine and prednisolone drug level of 30 ng/ml needed in the first 2 months post transplant reduced to 15 ng/ml thereafter.
Everolimus: 3-8 ng/ml trough concentration is needed.2
References:
Toutain P.L, Bousquet-Melou A.Bioavailability and its assessment. Journal of Veterinary pharmacology and therapeutics, published online on 2004 DEC,8th.
2021 uptodate. cited on 7th Nov. 2021.
Ben Lomatayo
3 years ago
Monitoring of the immunosuppressive therapy is essential part of kidney transplantation. This exercise is to ensure that the desired drug level is obtained and the patient is not over-immunosuppressed(=toxicity) and under-immunosuppressed(=rejection). Example of drug monitoring ;
1.Calcineurin inhibitor ; Tacrolimus is monitored best by trough level (C=0) , measuring the level before the next dose, 12 h or 24h after the last dose. Initially 8 to 12 ng/ml is desired tac level , after 6 months level of 6.3 to 8 max , but this is centre dependent. Cyclosporine is measured by both C = 0 and C2 which is the measurement 2 h after the dose .Usual level is in the range of 150 to 200 ng/ml and it is centre dependent
2.mTORi ; e.g. Everolimus / Sirolimus , the level of Everolimus range from 3 to 8 ng/ml depending whether it is used with CNI minimization protocol or elimination
3.Antiproliferative e.g. MPA, or Azathioprine. Measuring the level is not yet standard of practice
Bioavailability refers to the amount drug that research systemic circulation and site of the action after administration.
Doaa Elwasly
3 years ago
The aim of Therapeutic Drug Monitoring is to optimize pharmacotherapy by maximizing therapeutic efficacy, while minimizing adverse events. Cyclosporine
A prospective study showed that although C0 (trough concentration) levels of CsA correlated poorly with dose, Cmax was significantly correlated with dose, Area Under the Curve (AUC) and elimination half-life (t1/2).the 2 h post-dose concentration has been advocated as a single concentration monitoring alternative to C0.
Currently, most transplant centers measure a single steady-state CsA concentration as either a C0 predose trough or 2 hours postdose, while some conduct multiple measurements to determine CsA AUC estimates . Tacrolimus
Drug levels are obtained as predose (12 hours after previous dose) trough concentrations in whole blood . These trough levels correlate well with area under the curve representing an accurate measure of drug exposure Mycophenolic acid (MPA)
With trough concentration, plasma concentration of MPA is measured immediately before a dose, and only requires single simple possible association between C0 and decreased rejection in transplant recipients. On the otjer hand timing may not be accurate. Timing may vary from the “ideal” (12 h after last dose) by several hours. Sirolimus (SRL)
the first measurements should not be taken before day 4 after inception of, or change in therapy.It is recommended to monitor Cmin,ss weekly for the first month and twice weekly for the next month, targeting a 5 to 15 μg/L range if CsA is being also used at Cmin,ss concentrations of 75 to 150 μg/L. Everolimus (EVL)
It has narrow therapeutic index. The EVL Cmin is a good marker of EVL exposure (AUC), and correlates with pharmacological response and clinical outcomes.
The recommended therapeutic range for EVL is a trough concentration of 3 to 8 ng/mL, because concentrations over 3 ng/mL have been associated with a decreased incidence of rejection, and concentrations >8 ng/mL with increased toxicity.
Reference:
Ana Luisa Robles Piedras, Minarda De la O Arciniega and Josefina Reynoso Vázquez (February 13th 2013). Clinical Pharmacology and Therapeutic Drug Monitoring of Immunosuppressive Agents, Current Issues and Future Direction in Kidney Transplantation, Thomas Rath, IntechOpen, DOI: 10.5772/54910. Available from: https://www.intechopen.com/chapters/42876 Bioavailability refers to the extent and rate by which the active moiety (drug or metabolite) enters systemic circulation, where it access it’s site of action.
It is 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 have clinical importance; therefore, knowing whether drug formulations are equivalent is essential.
Reference
Jennifer Le , Drug Bioavailability .MSD Mannual professional version .Oct 2020
With SANDIMMUNE, trough levels were used for TDM as it was found that C0 levels correlated better with toxic complications. But with NEORAL, C2 levels corerlated better with drug effects due to better consistent absorption. But for the sake of uniformity, majority of the centers use trough levels.
For tacrolimus, C0 levels are the ones which are usually done, C2 levels have not been shown to be superior to C0 tacrolimus levels. (1)
Although some studies have shown that C2 tacrolimus levels are beneficial as a predictor of acute rejection. (2)
1) Jorgensen K, Povlsen J, Madsen S, et al. c2 (2-h) levels are not superior to trough levels as estimates of the area under the curve in tacrolimus-treated renal transplant patients. Nephrol Dial Transplant 2002.;17:1487-90. 2) Scholten EM, Cremers SCLM, Shoemaker RC, et al. AUC guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients. Kidney Int 2005;67:2440-2447.
as regard cyclosporin C0 is popular than C2, but recently C2 monitoring is found to have better impact on graft survival especially in the 1st 6 months post transplant
Monitoring of C0 is more common in practice, more popular and more convenient to the patient, but some patients have poor absorption of the drug and thus C2 will correlate better with clinical outcome.
It was found that higher C2 is associated with lower rate of acute rejection (1)
Target C0 800-1000 in first 3 m then 400-600 thereafter
C0 is more used than C2. C2 monitoring correlates with better graft survival in the first 6 months post-Tx. C0 is used for monitoring Tacrolimus and not C2.
Bioavailability of a drug in simple language would be the portion of the drug which becomes completely available to its intended destination, that is the systemic circulation
The bioavailability is the amount of drug reaching the general circulation from the delivery system being used. The bioavailability of a drug administered by the intravenous route is 100%.
bioavilability of the drug: defined as the extent and the rate at which the active metabolite of the drug enter the systemic circulation and reach the site of action.
Bioavailability is the per cent of the metabolically active substance that reaches the target site of action in relation to the total amount of drug given to the patient (1, 2).
It is the outcome of the pharmacokinetics of the drug (absorption, distribution, metabolism, and elimination). All of which affect the drug’s effect by altering the drug’s concentration at its site of action.
References:
1) Currie GM. Pharmacology, Part 2: Introduction to Pharmacokinetics. J Nucl Med Technol. 2018 Sep;46(3):221-230.
2) Herkenne C, Alberti I, Naik A, Kalia YN, Mathy FX, Préat V, Guy RH. In vivo methods for the assessment of topical drug bioavailability. Pharm Res. 2008 Jan;25(1):87-103.
Mycophenolic acid (MPA) trough levels are poorly correlated with AUC and are not recommended (1).
What are the risks of high MPA level?
There is some studies that suggest a relationship between the degree of mycophenolate exposure (eg, dose, total mycophenolate AUC, free mycophenolate AUC, metabolite(s) AUC, trough concentrations) and the development of bone marrow suppression (most commonly anaemia or leukopenia).
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
TDM of MPA is not usually done although it is important to avoid risk of toxicity, get levels according to immunological risk and posttransplant period and to be balanced with tacrolimus level “high tacrolimus target probably need to be counterbalanced by low target MPA”
high MPA levels increase the risk of over immunosuppression which increase risk of infections and malignancy (not caused by calcineurin inhibitors only)
Bentata, Y. (2020). Mycophenolates: The latest modern and potent immunosuppressive drugs in adult kidney transplantation: What we should know about them?. Artificial organs, 44(6), 561-576.
MPA monitoring is not yet standard of care according to last European Renal Practice guideline. High MPA is associated with GIT upsets, in particular diarrhoea , myelosuppression. some reports of neurotoxicity in Japan. Plus increase risk of infections. Diarrhoea is common reason for discontinuation of MPA and this is associated with increase risk of rejection
Bioavailability
is the fraction of the administered dose of a drug that reaches the systemic circulation .For intra venous route bioavailability is 100%while in other routes of administration ,it could be lower .It may be influence by the first pass effect .
Therapeutic equivalence
indicates that drug products, when are given to the same patient at the same dosage, provide the same therapeutic and adverse effects .
Some immunosuppressant drugs such as cyclosporine, which have different products. Also, the difference between its therapeutic and toxic or ineffective concentration is small and considered to have a narrow therapeutic window .
Bioavailability is usually assessed by determining the area under the plasma concentration . The most reliable measure of a drug’s bioavailability is AUC. AUC is directly proportional to the total amount of unchanged drug that reaches the systemic circulation .
Accordingly immunosuppressant agent should be monitored by assessing their blood level .The peak level of cyclosporine (2hrs after dosing C2) may correlate better with drug exposure than trough level(C0) .The trough level (drawn immediately ,preceding the next dose) expresses an adequate drug exposure . For mTOR inhibitor ,the trough level correlate well with therapeutic effects as well . The therapeutic drug monitoring is not routinely performed in case of Mycophenolic acid .The blood level of Azathioprine cannot determine its effectiveness .
Reference ;
1. Al Ameri MN, Whittaker C, Tucker A, Yaqoob M, Johnston A: A survey to determine the views of renal transplant patients on generic substitution in the UK. Transpl Int 2011;24:770–779. [PubMed] [Google Scholar]
2. Rehman S, Wen X, Casey MJ, Santos AH, Andreoni K: Effect of different tacrolimus levels on early outcomes after kidney transplantation. Ann Transplant 2014;19:68–75. [PubMed] [Google Scholar]
3. Taber DJ, Baillie GM, Ashcraft EE, et al.: Does bioequivalence between modified cyclosporine formulations translate into equal outcomes? Transplantation 2005;80:1633–1635. [PubMed] [Google Scholar]
4. Molnar AO, Fergusson D, Tsampalieros AK, et al.: Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis. BMJ 2015;350:h3163. [PMC free article] [PubMed] [Google Scholar]
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
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
monitoring of cyclosporine and tacrolimus drug level is important part of transplantation because of interpatiiont and intrapatient variation .
there is arelation between drug level and rejection episodes . this is an area of confusion because of various assay available and different sample used ( plasma , whole blood ).
When Sandimmune was introduced, the trough level of cyclosporine (Co ), rather than the peak level(C2), was measured because its correlate better with toxic complications. More sophisticated techniques of monitoring is constructed to calculate the AUC, which reflects the bioavailability of the drug and may theoretically allow for more precise and individualized patient management. Although attractive, but costy and inconvenience.
Further studies suggest that c2 rather than c0 correlate better with clinical event.Therefore the c2 monitoring become routine .
For tacrolimus, the trough levels are usually used
for monitoring, and this level is an adequate approximation of drug exposure: some programs use peak tacrolimus levels.
Cyclosporine level can be measured in plasma or whole blood. Whole blood is the recommended specimen type
Several methods are currently available to measure cyclosporine, and each differs in specificity for parent compound. High-performance liquid chromatography (HPLC) is the most specific method for measuring unmetabolized parent cyclosporine and is considered the reference method ( but is expensive )..
Immunoassays, which use monoclonal antibodies against cyclosporine, are commonly used and have largely replaced HPLC because they can be performed on automated chemistry analyzers. The most commonly used immunoassay to measure cyclosporine in whole-blood samples is the Abbott (Chicago, IL) fluorescence polarization immunoassay (FPIA), which has significant cross-reactivity with cyclosporine metabolites and overestimates cyclosporine by as much as 45% .
For monitoring of tacrolimus concentrations, most laboratories use the Abbott monoclonal antibody-based microparticle enzyme immunoassay (MEIA) that can be performed on an automated instrument (IMx). This assay permits accurate estimation of tacrolimus levels as low as 2 ng/mL.
Abbott has also developed a chemiluminescent microparticle immunoassay (CMIA) that is available on the ARCHITECT family of instruments with a reported detection limit of less than 1 ng/mL. New methodologies employ electrochemiluminescence immunoassay (ECLIA) techniques similar to CMIA with a reported detection limit of 0.5 ng/mL utilizing a 300^L sample size.
1- Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
2- Currie GM. Pharmacology, Part 2: Introduction to Pharmacokinetics. J Nucl Med Technol. 2018 Sep;46(3):221-230.
Monitoring immuno suppressive drugs level is very crucial in transplant patient especially those with Narrow safety margin like CNI and mTORi
We can measure C max and trough level to access toxicity and efficacy
Bioavailability is the percent of drug that Reach its site of action
Bioavailability refers to the extent a substance or drug becomes completely available to its intended biological destination . 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.
Drug bioavailability is the fraction of the administered dose that reaches the systemic circulation. For the clinician, the most relevant consideration is the percentage of active drug that reaches the central compartment. Bioavailability does not take into account the rate at which the drug is absorbed. Bioavailability is affected by factors that influence absorption.
For the majority of currently used immunosuppressive drugs, measurement of total drug exposure by determination of the dose-interval area under the concentration curve (AUC) seems to provide more useful information for clinicians in terms of concentration-exposure and exposure-response as well as reproducibility.
immunsuperssive therapy post transplantion very crucial to prevent rejection and maintian good immune response with better graft and patient survival ,drug monitroing also help in assess the potency of the regular immunsuppression with less side effects by using drug monitroing that will refect the optimal theraputic level with aviodnace of under supperssion or oversuppression,CNI trough otr C2 level to monitor the tacrolimus orcyclsoprine trough level ,sirolimus , everolimus trough
Drug bioavailability refere to the rate and range of active molecule absorption, when it becomes available in the systemic circulation or at the site of drug action, respectively. Drug bioavailability after oral administration is affected by many 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
Immunosuppression drugs [immunosuppresants] are impotant in transplant medicine as they reduce the incidence of organ rejection, acute and chronic, in transplant recipients.These medicines must be in the right concentration in the recipient, as subtherapeutic doses can cause rejection, and supra-therapeutic levels are toxic to the organs and predispose to infections. These medicines have a narrow therapeutic index, and have differing inter-individual variability, and as a result require monitoring. Factors that can cause inter-individual variability include gender, body mass, drug-nutrient interactions, drug-disease interactions, infection.
Imunosupressants are monitored nby therapeutic drug monitoring [TDM]. TDM is themeasurement and interpretation of the concentration of these drugs in t biological fluids, with the aim of predicting oprgan responses. They are part of transplant protocols.TDM is done for Tacrolimus, Sirlimus, Mycophenolate mofetil and cyclosporine.
Bioavability [of a drug] is the extent and rate at which the active moiety of the drug or its metabolite, enters the systemic circulation and is thus able to access the site of action. Bioavailability ois greatly determined by the properties of the dosage form, and these properties depend on the manufacture and design of the medicine. Several factors can affect bioavailabity of a drug, thus causing low availability of the medicine, and they include age, gender, oral dosage form of a medicine, physicalactivity, stress disorders, and transit time in the gut.
References
CALCINURINE INHIBITORS;TACROLIMUS OR CYCLISPORINE LEVELS NEED ROUTINE MONITORING .TACROLIMUS WHOLE BLOOD LEVEL IS MONITORED BY 12 -HOUR TROUGH CONCENTRATION FOR IMMEDIATE-RELEASE FORM AND 24 HOUR TROUGH CONCENTRATION FOR EXTENDED RELEASE ONES.TARGET LEVELS IN PATIENTS RECIEVING ANTITHYMOCYTE DEPLETION ARE 7-10 ng/mL FOR THE FIRST MONTH FOLLOWING Tr AND3-7 ng/mL FOR THE NEXT MONTHS.FOR THOSEWHO DID NOT RECIEVE ANTITHYMOCYTE DEPLETION,TARGET LEVELS ARE 8-10 ng/mL FOR THE FIRST 3 MONTHS AFTER Tr AND 3-7 ng/mLFOR NEXT MONTHS.
IN PATIENTS ON CYCLOSPORINE,WHOLE BLOOD 12 HOUR TROUGH CONCENTRATION IS ESTIMATED.TARGET LEVELS ARE 200-300 ng/mL IN FIRST 3 MONTHS FOLLOWING Tr&50-150 ng/mL FOR NEXT MONTHS.
PATIENTS RECIEVING AZATHIOPRINE WITH SIGINICANT BONE MARROW SUPPRESSION,THE ENZYME THIOPURINE METHYLTRANSFERASE IS TESTED AND IF ITS DEFICIENCY DETECTED,THE DRUG SHOULD BE DISCONTINUED.
MMF IS DISCONTINUED IN CASE OF PERSISTENT DIARRHOEA.CURRENTLY,NO LAB MONITORING AVAILABLE FOR ANTIMETABOLITE AGENTS.
BIOAVAILABILITY:
IT DESCRIBES THE STATE OF COMPLETE AVAILABILITY OF SUBSTANCE OR MEDICATION FOR THE TARGET SITE OR SITE OF DESIRED ACTION.IT COULD BE DEFINEDAS THE UNCHANGED ACTIVE FORM OF A DRUG THAT REACHES SYSTEMIC CIRCULATION WITH THE ASSUMPTION THAT 100% OF THE ACTIVE DRUG IN CIRCULATION WILL REACH ITS TARGET SITE.INTRINSIC FACTORS AFFECTING BIOAVAILABILITY INCLUDE ACTIVATION METABOLISM,DRUG RECEPTORS,ABSORPTIONAND ROUT OF ADMINSTRATION.EXTRINSIC FACTORS INCLUDE INTERACTION WITH OTHER DRUG OR FOOD.
REFERENCES:
KIDIGO CLINICAL PRACTICE GUIDELINES FOR THE CARE OF KIDNEY TRANSPLANT RECIPIENTS ,Am J Transplant ,2009;9 suppl 3;s1
Schiff J,Cole E, Cantarovich M, Therapeutic monitoring of calcinurine inhibitors for the nephrologist .Clin J Am Soc Nephrol,2007;2;374
Chow SC,BIOAVAILABILITY AND BIOEQUIVALENCE IN DRUG DEVELOPMENT,WILEY INTERDISCIP REV COMPUT STAT,2014;6(4):304-312
Mansoor A,Mahabadi N.stat pearls treasure island:JUL 26,2021,VOLUME OF DISTRIBUTION.9 (Pub Med)
Bioavailability (F) is defined as the rate and extent to which the active constituent or active moiety of a drug is absorbed from a drug product and reaches the circulation
Azathioprine, steroids, anti-lymphocyte globulin, and OKT3Monitoring the blood or plasma concentration of these drugs is not considered worthwhile as they all have relatively wide therapeutic indices. The three agents are generally given in fixed doses and are not subjected to therapeutic drug monitoring.
cyclosporine is monitored by A trough level is the lowest concentration reached by a drug before the next dose is administered. For example, if cyclosporine is given twice a day, a blood sample is usually drawn 12 hours after the last dose, before a new dose is given.
Tacrolimus is usually taken twice a day at set intervals before or after meals. When a person takes a dose, blood concentrations rise and peak within about 2 to 3 hours and then begin to slowly drop. The blood test is usually measured as a ‘trough’ level.
■Bioavailability refers to the extent and rate at which the active moiety of a drug 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.
■Causes of low bioavailability :
1-Many drugs may be metabolized before adequate plasma concentrations are reached.
Orally administered drugs must pass through the intestinal wall and then the portal circulation to the liver, both are common sites of firstpass metabolism (metabolism that occurs before a drug reaches systemic circulation).
Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs.
2- Insufficient time for absorption in the gastrointestinal (GI) tract is a common cause of low bioavailability.
If the drug does not dissolve readily or cannot penetrate the epithelial membrane (for example if it is highly ionized and polar), time at the absorption site may be insufficient.
In such cases, bioavailability tends to be highly variable as well as low.
3-Chemical reactions that reduce absorption can decrease bioavailability
4- Others :
Age, sex, physical activity, genetic phenotype, stress, disorders (eg, achlorhydria, malabsorption syndromes), or previous GI surgery (eg, bariatric surgery) can also affect drug bioavailability.
■ASSESSING the bioavailability:
Bioavailability is usually assessed by determining the area under the plasma concentration–time curve (AUC).
The most reliable measure of a drug’s bioavailability is AUC.
AUC is directly proportional to the total amount of unchanged drug that reaches systemic circulation.
Bioavailability determinations based on the peak plasma concentration can be misleading because drug elimination begins as soon as the drug enters the bloodstream.
Peak time (when maximum plasma drug concentration occurs) is the most widely used general index of absorption rate; the slower the absorption, the later the peak time.
For drugs excreted primarily unchanged in urine, bioavailability can be estimated by measuring the total amount of drug excreted after a single dose
_________________________________
●●☆☆IMMUNOSUPPRESSION MONITORING☆☆●●
Regarding
1- CNI :
TACROLIMUS :
Monitoring Parameters
Renal function, hepatic function, serum electrolytes (calcium, magnesium, phosphorus, potassium) periodically in patients with heart failure, bradyarrhythmias, or concomitant medications known to prolong the QT interval),
blood glucose (frequently).
Monitor BP (3 times/week for first few weeks, then gradually decrease frequency as patient stabilizes).
Patients receiving IV tacrolimus should be monitored for signs/symptoms of hypersensitivity/anaphylactic reactions for at least the first 30 minutes following the start of the infusion, and frequently thereafter.
Monitor for QT prolongation; consider echocardiographic evaluation in patients who develop renal failure, electrolyte abnormalities, with heart failure, bradyarrhythmias, or concomitant medications known to prolong the QT interval or clinical manifestations of ventricular dysfunction.
Monitor for signs/symptoms of infection, neurotoxicity, and secondary malignancy.
Closely monitor tacrolimus levels to assist in dose adjustment, monitor compliance, prevent organ rejection, and reduce drug-related toxicity.
Whole blood concentrations should be used for monitoring (trough for oral therapy drawn typically within 30 minutes prior to the next dose) frequency varies depending on transplant type, time since transplantation, and clinical situation.
NB in renal as well as liver tx ptns :
Tacrolimus serum levels may be falsely elevated in infected liver transplant patients due to interference from
beta-galactosidase antibodies.
●☆☆Reference Range in renal Tx: ☆☆●
Whole blood trough concentrations:
■Immediate release:
In combination with azathioprine (if used):
Months 1 to 3: 7 to 20 ng/mL.
Months 4 to 12: 5 to 15 ng/mL.
In combination with mycophenolate mofetil/IL-2 receptor antagonist (eg basiliximab):
4 to 11 ng/mL.
In combination with mTOR inhibitor (everolimus):
4 to 8 ng/mL for the first 2 months post-transplant
followed by
3 to 5 ng/mL thereafter (Sommerer 2016).
■■Extended release (Astagraf XL):
Adult:
●With basiliximab induction:
Month 1: 7 to 15 ng/mL.
Months 2 to 6: 5 to 15 ng/mL.
>6 months: 5 to 10 ng/mL.
●Without basiliximab induction:
Month 1: 10 to 15 ng/mL.
Months 2 to 6: 5 to 15 ng/mL.
>6 months: 5 to 10 ng/mL.
●●CYCLOSPORIN●●
Monitor plasma concentrations, renal function (serum creatinine and BUN), and blood pressure periodically and following the addition, modification, or deletion of other medications.
Monitor for hypersensitivity reactions (IV cyclosporine). Monitor for signs/symptoms of hepatotoxicity, secondary malignancy, diabetes mellitus, infection.
Monitor for progressive cognitive or motor deficits; magnetic resonance imaging may be required for diagnosis of posterior reversible encephalopathy syndrome (PRES).
Rtx that presented with Nephrotic syndrome ( these data is for nephrotic syndrome in general ):
Baseline blood pressure (2 readings within 2 weeks), fasting serum creatinine (at least 3 levels within 2 weeks), creatinine clearance, urinalysis, CBC, liver function, serum uric acid, serum potassium, and malignancy screening (eg, skin, mouth, lymph nodes).
Biweekly monitoring of blood pressure for initial 3 months and then monthly thereafter, frequent monitoring of renal function and periodic cyclosporine trough levels are recommended during therapy.
Consider renal biopsy in patients with steroid dependent minimal change nephropathy who have been maintained on therapy >1 year.
Transplant patients: Cyclosporine trough levels, serum electrolytes, renal function, hepatic function, blood pressure, lipid profile, blood sugar, and HbA1c
Therapeutic trough range in solid organ transplant (kidney, liver, heart): Not absolutely defined, dependent on organ transplanted, time after transplant, organ function and CsA toxicity:
General range of 100 to 400 ng/mL; refer to institutional protocol for specific therapeutic ranges
Toxic level: Not well defined, nephrotoxicity may occur at any level
Recommended cyclosporine therapeutic ranges when administered in combination with everolimus for renal transplant (Zortress product labeling 2018):
Month 1 post-transplant: 100 to 200 ng/mL
Months 2 and 3 post-transplant: 75 to 150 ng/mL
Months 4 and 5 post-transplant: 50 to 100 ng/mL
Months 6 to 12 post-transplant: 25 to 50 ng/mL
☆●☆Alternative monitoring (renal transplant): Two-hour post cyclosporine dose level (obtaining a level 2 hours after administration correlates well with drug exposure throughout the 12-hour dosing interval [Schiff 2007])
IL-2 induction therapy (2-hour post cyclosporine dose level):
Month 1 and 2: >1,500 ng/mL
Month 3: 1,200 to 1,400 ng/mL
Month 4 to 12: 600 to 1,000 ng/mL
Month >12: ~800 ng/mL
Antithymocyte globulin (rabbit) induction therapy (2-hour post cyclosporine dose level):
Month 1 to 3: 1,000 to 1,200 ng/mL
Month 4 to 12: 600 to 1,000 ng/mL
Month >12: ~800 ng/mL
In most patients treated with cyclosporine, we monitor whole-blood 12-hour trough (C0) concentrations [4]. With this approach, our C0 target levels are the following:
●200 to 300 ng/mL in months 1 to 3 after transplantation
●50 to 150 ng/mL for subsequent months
Although monitoring of trough levels (12 hours postdose) of cyclosporine is common practice, there is a poor correlation between clinical outcome and drug exposure as assessed using this strategy. Thus, in some patients (eg, patients suspected of having poor cyclosporine absorption), we monitor two-hour postdose cyclosporine (C2) levels [63]. Among kidney transplant recipients, the C2 level may correlate more closely with exposure, with higher C2 concentrations being associated with decreased acute rejection rates in the first year posttransplant [64-66]. However, C2 monitoring is often more difficult and less convenient for the patient. Our C2 target levels are the following:
●800 to 1000 ng/mL in months 1 to 3 after transplantation
●400 to 600 ng/mL for subsequent months
MMF and EC-MPS are similar in efficacy and safety [68,69].
We prefer EC-MPS over MMF because EC-MPS may be associated with fewer gastrointestinal side effects among certain groups of patients (eg, patients with indigestion, diabetes, those treated with glucocorticoids, or patients converted from MMF to EC-MPS between 6 to 12 months posttransplant)
MMF is now the best antimetabolite used to minimize rejection according to 2009 KDIGO guidelines.
However, we do not use mycophenolate in female recipients of childbearing age unless they are on long acting contraception, have undergone surgical sterilization procedures, or have absolute infertility. Mycophenolate is teratogenic, and its use is contraindicated in pregnancy.
Thus, in these patients, we prefer to use azathioprine, which does not seem to have a detrimental effect on fertility or pregnancy.
■■ AZATHIOPRINE
The usual maintenance dose for azathioprine is 1.5 mg/kg per day, although it is 2.5 mg/kg at some centers.
CBC with differential and platelets (weekly during first month, twice monthly for months 2 and 3, then monthly thereafter; monitor more frequently with dosage modifications), total bilirubin, liver function tests (every 3 months), CrCl, monitor for signs/symptoms of infection and malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss).
Azathioprine has been associated with skin cancer with long-term use after kidney transplantation.
Patients taking azathioprine for a prolonged time period should avoid sun exposure and be monitored for skin cancer regularly.
Thiopurine S-methyltransferase (TPMT) genotyping or phenotyping: Consider testing for TPMT deficiency, particularly in patients with abnormally low CBC unresponsive to dose reduction. TPMT genotyping or phenotyping may assist in identifying patients at risk for developing toxicity (CPIC [Relling 2019]).
Nudix hydrolase 15 (NUDT15) genotyping: Consider genotyping for NUDT15 deficiency in patients who experience severe bone marrow toxicities or repeated myelosuppressive episodes. NUDT15 genotyping may assist in identifying patients at risk for developing toxicity (CPIC [Relling 2019]).
■■GLUCOCORTICOIDS
Monitoring to:
• BP
• weight
• serum glucose
• Electrolytes
• Growth in pediatric patients
•Presence of infection
• Bone mineral density
• Assess HPA axis suppression
(eg, ACTH stimulation test,
morning plasma cortisol test,
urinary free cortisol test),
•Hgb
•Occult blood loss
•Chest x-ray (at regular
intervals during prolonged
therapy)
•IOP with therapy >6 weeks, eye examination (periodically during therapy [AASLD (Mack 2020)]).
■■ATG ( RABBIT)
Monitoring Parameters
Lymphocyte count (total lymphocyte and/or T-cell subset), CBC with differential and platelet count; vital signs during administration; signs and symptoms of infection
Solid organ transplant: Absolute CD3 count (cells/µL) monitoring and CD3 based dosing has been considered in renal and heart transplant recipients. It may be beneficial in certain patient populations but is not routinely recommended or utilized. Dose adjustments have been recommended based on the CD3 count (Krasinska 2002).
■■Rituximab :
Monitoring Parameters
•CBC with differential and platelets (obtain prior to treatment and prior to each treatment course, and at weekly to monthly intervals and more frequently in patients with lymphoid malignancies, or at 2- to 4-month intervals in rheumatoid arthritis patients, granulomatosis with polyangiitis and microscopic polyangiitis).
•Continue to monitor for cytopenias after the final rituximab dose and until resolution.
•Monitor electrolytes (in patients at risk for tumor lysis syndrome [TLS]), renal function (in patients at risk for TLS or nephrotoxicity), fluid/hydration status balance. •Monitor BP and vital signs.
•Hepatitis B virus reactivation screening: Screen all patients for hepatitis B virus (HBV) infection prior to therapy initiation (eg, hepatitis B surface antigen [HBsAG] and hepatitis B core antibody measurements).
•Screen patients with multiple sclerosis for latent infections (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline). In addition, carriers and patients with evidence of current infection or recovery from prior hepatitis B infection should be monitored closely for clinical and laboratory signs of HBV reactivation and/or infection during therapy and for up to 2 years following completion of treatment.
•The American Society of Clinical Oncology HBV screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with HBsAg, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results.
Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring and follow-up. Monitor for signs of active hepatitis B infection.
•••Monitor closely for infusion-related reactions.
•Perform cardiac monitoring during and after rituximab infusion (in rheumatoid arthritis patients and in patients with preexisting cardiac disease, a history of arrhythmia or angina, or if clinically significant arrhythmias develop during or after subsequent infusions). Monitor for signs/symptoms of bowel obstruction/perforation (abdominal pain, vomiting), tumor lysis syndrome, and/or mucocutaneous skin reactions. Monitor for signs or symptoms of progressive multifocal leukoencephalopathy (focal neurologic deficits, which may present as hemiparesis, visual field deficits, cognitive impairment, aphasia, ataxia, and/or cranial nerve deficits); if progressive multifocal leukoencephalopathy is suspected, obtain brain MRI scan and lumbar puncture.
REFERENCES
(4) https://pubmed.ncbi.nlm.nih.gov/19845597/
(9)
https://pubmed.ncbi.nlm.nih.gov/17509448/
(11)
https://pubmed.ncbi.nlm.nih.gov/11317972/
(14)
https://pubmed.ncbi.nlm.nih.gov/18808409/
(63)
https://pubmed.ncbi.nlm.nih.gov/17699437/
(64)
https://pubmed.ncbi.nlm.nih.gov/12023608/
(69)
https://pubmed.ncbi.nlm.nih.gov/14974945/
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https://pubmed.ncbi.nlm.nih.gov/9808489/
(112)
https://pubmed.ncbi.nlm.nih.gov/20056756/
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https://pubmed.ncbi.nlm.nih.gov/9808489/
It is clearly known than all patient after transplantation should be on immunosuppressants for maintaining their graft functioning . Immunosuppressants require therapeutic drug monitoring because of their narrow therapeutic index and significant inter-individual variability in blood concentrations. This variability can be because of factors like drug-nutrient interactions, drug-disease interactions, renal-insufficiency or inflammation . Drug monitoring is widely practiced especially for cyclosporine, tacrolimus, sirolimus and mycophenolic acid.
1. Cyclosporine
Therapeutic monitoring of immunosuppressive therapy with cyclosporine is a critical requirement because of intra- and inter-patient variability of drug absorption, narrow therapeutic window and drug induced nephrotoxicity.
Mycophenolic acid (MPA)
Some reasons for therapeutic drug monitoring of MPA during post-transplant period include: relationship between MPA pharmacokinetic parameters and clinical outcomes, Inter-patient pharmacokinetic variability for MPA despite fixed MMF doses, alternations of MPA pharmacokinetics during the first months after transplantation, drug- drug interaction and influence of kidney function on MPA pharmacokinetic.
Sirolimus
A recent review of the pharmacokinetics of sirolimus suggested a therapeutic range of 5 to 10 μg l−1 in whole blood. However, the only consensus guidelines published on the therapeutic monitoring of sirolimus concluded that there was not enough information available about the clinical use of the drug to make recommendations.
Tacrolimus
Sudies have shown, in kidney and liver transplant patients, significant associations of low tacrolimus concentrations with rejection and of high concentrations with nephrotoxicity. Although the feasibility of a limited sampling scheme to predict AUC has been demonstrated, as yet, trough, or pre-dose, whole blood concentration monitoring is still the method of choice.
Bioavailability
Is defined as the extent a substance or drug becomes completely available to its intended biological destination. 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 in other words , bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered. This definition assumes 100% of the active drug that enters systemic circulation will successfully reach the target site.
References
Spector R, Park GD, Johnson GF, Vesell ES. Therapeutic drug monitoring. Clin Pharmacol Ther. 1988;43:345–353. [PubMed
1.
Currie GM. Pharmacology, Part 2: Introduction to Pharmacokinetics. J Nucl Med Technol. 2018 Sep;46(3):221-230. [PubMed
Bioavailability of a drug means the fraction of this medication that reaches the systemic circulation. For example the bioavailability of intravenous drugs is 100% while bioavailability in other routes is less due to the effect of first pass metabolism and intestinal absorption.
Due to the narrow therapeutic index of the immunosuppression drugs and drug drug interactions, they should be monitored by therapeutic drug monitoring (TDM), which means frequent measuring of drug level in the blood.
Examples for drugs that should be monitored include cyclosporine, MMF, Tacrolimus, Sirolimus.
To demonstrate the importance of TDM of these drugs, Tacrolimus for example , high concentration is associated with nephrotoxicity while low concentrations is associated with increased risk of rejection.
Ref:
A Review on Therapeutic Drug Monitoring of Immunosuppressant Drugs (nih.gov)
Kidney transplant recipients need appropriate maintenance immunosuppression to preserve their graft. Under-immunosuppression or over- immunosuppression are associated with high rate of rejection or infection and malignancy, respectively. Proper immunosuppression needs proper dose of drug. But because of inter or intra-variability among people or different forms of immunosuppression drug, it is difficult to reach. For this purpose, tandem drug monitoring is performed after transplantation based on time after Tx at regular intervals. Trough level is used for Tacrolimus, Sirolimus and Everlimus. For cyclosporine, C2 is performed in addition to C0 and is better.
Bioavailability means level of drug that enters into circulation and at the site of action of drug. Bioavailability of an oral dose of drug is determined by comparison with IV administration of the same drug. This topic is important when using generic immunosuppression drugs instead of original brand because of their price. MMF is usually administered at fix dose without measurement of its drug level. New methods to avoid over-immunosuppression such as torque teno virus (TTV) load or virus-specific T cells (Tvis) level can be used especially in children.
References:
1. Ahlenstiel-Grunow, T., Pape, L. Novel ways to monitor immunosuppression in pediatric kidney transplant recipients—underlying concepts and emerging data. Mol Cell Pediatr 8, 8 (2021).
2.Tsipotis E, Gupta NR, Raman G, Zintzaras E, Jaber BL. Bioavailability, Efficacy and Safety of Generic Immunosuppressive Drugs for Kidney Transplantation: A Systematic Review and Meta-Analysis. Am J Nephrol. 2016;44(3):206-18.
Immunosuppressive drugs used to reduce immune response.
Common transplant immunosuppression drugs are:
1-Glucocorticoid.
2—Calcineurin inhibitor.
3-Antimetabolic agent.
4-Biological agent.
These drugs are effective at therapeutic dose but variation exist with their narrow
therapeutic dose which can lead to adverse effect.
Therapeutic drug monitoring is needed to check for concentration, that’s not too low or
high, with risk of infectivity with low and toxicity with high dose. In therapeutic drug
monitoring plasma concentration is measured and dose adjusted to achieve goals.
This monitoring with blood concentration done with following drugs of response and side
effect in addition to vital sign and basic blood chemistry ,i.e. CBC ,RBG ,RFT AND LFT.
As some drugs cause bone marrow suppression. , anemia, renal impairment and liver
failure.
Cyclosporine :TDM
1-Troughh concentration:
Most transplant center use A CSA concentration either C0 predose trough or 2hours post
dose.
2-Area under the curve (AUC):
MULTPLE MEASURMENT NEEDED, TIME CONSUMMING.
3-Two hours post dose concertation (C2):
More simple by measuring blood CSA concentration at 2hours after dose.
4-Bayesian forecasting:
Calculate dosage regimens and pharmacokinetic parameters and predict drug
concentration by blending population value with patient specific values.
The therapeutic level serum concentration is 50-150 ng/ml.
Tacrolimus (TRL):
Therapeutic rang for TRL in most transplant center is 5-20ng/ml in blood.
Trough or predose whole blood concentration is used (12hours after previous dose).
Mycophenolic acid (MPA):
Though current labeling information for MMF does not indicate any need for therapeutic
monitoring of plasma MPA, there’s difference in protocol in transplant center, depend on
availability of monitoring, in high risk patient or those with adverse effect.
With trough concentration, plasma concentration of MPA measured immediately before
dose.
Sirolimus (SRL):
The appropriate SRL trough concentration at steady state (Cmin, SS).
Measurement should be done after 4days after induction or change of therapy..
After monitor Cmin, SS weekly for first month and biweekly for the next month, targeting
5 to 15mg/l.
Everlimus (EVL):
The EVL, Cmin is good surrogate for EVL.
Recommended therapeutic range for EVK is trough concentration of 3-8ng/ml.
Azathioprine:
monitoring the blood or plasma concentration of these drugs is not considered
worthwhile as they all have relatively wide therapeutic indices. The three agents are
generally given in fixed doses and are not subjected to therapeutic drug monitoring.
However, a case can be made for the measurement of the activity of the enzyme
thiopurine methyl transferase (TPMT) as an adjunct to azathioprine therapy.(2).
Daclizumab and basiliximab:
Due to wide therapeutic index, little to be gained from therapeutic drug monitoring for these agents (3).
Bioavailability:
Is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered (4).
Reference:
1-Ana Luisa Robles .Minarda De La Arciniega et al, Clinical pharmacology and
therapeutic drug monitoring of immunosuppressive Agent, Feb.DOI, 105772/54910.
2- Atholl Johnston and David W Holt. Therapeutic drug monitoring of immunosuppressant
drugs. Br J Clin Pharmacol. 1999 Apr; 47(4): 339–350.
3-Atholl Johnston and David W Holt. Therapeutic drug monitoring of immunosuppressant
drugs. Br J Clin Pharmacol. 1999 Apr; 47(4): 339–350
4- Gary Price; Deven A. Patel. Drug Bioavailability. Stat Pearls Publishing; 2021 Jan-.
How to monitor immunosuppression medications
Tranplantation successful management depends on strong knowledge with immunosuppressant medications and its side effects
The conventional triple immunosuppressive medications are steroids,mmf and tacrolimus
With or without induction upon certain indication which either depleting (ATG)Or non depleting (basilixmab)
Over immunosuppressed patients are exposed to complications like infections and malignancy
On the other hand under immunosuppressed patients are exposed to rejection
Patients who had accepted levels of immunosuppressant medications are still exposed to its complications
Immunosuppressive medications has narrow therapeutic levels
Therapeutic levels measured by multiple samples at regular intervals then drawing acurve of exposure (AUC)
some drugs Cmin(trough) have strong correlation with AUC like tacrolimus,sirolimus and evrolimus
Others C2 have more correlation to AUC like cyclosporine (but for standardization still C0 is the test of choice in clinical practice)
But on the other hand there’s drugs have different pharmacokinetics and dynamic with multiple peaks so to measure it’s therapeutic levels you have to withdraw multiple samples to define AUC like MMF so it’s not routinely done in clinical practice although it’s important to be measured to avoid its toxicity and to be sure that your patients are not underimmune suppressed specially in special circumstances like steroid free and CNI free regimens
Also recent study..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
So measuring MMF levels (do it or not),best way to measure it and when to decrease it after awhile of kidney tranplantation is still unanswered questions
Monitoring immune suppression medications not only by measuring its level in blood but also monitoring its complications and measure risks against benefits in every single day
And decide when to stop,add and shift from drug to another
For example… cyclosporine can cause gingival hyperplasia which may cause sever depression and affect patient compliance
Also tacrolimus can cause serious alopecia
Mtor can cause pneumonitis and significant proteinuria
Steroids can cause proximal myopathy and sever osteoporosis
HPLC assay technique is the best technique to measure drugs level(whole blood) but immune assay still the most commonly used which measure drug and its metabolites so it overestimate its level
Bioavailability is that fraction of the administered drug which reaches systemic circulation. It can be calculated by diving the AUC of oral (or other route – subcutaneous, intramuscular etc) drug by AUC of intravenous drug and multiplying by 100.
My own reflection from clinical practice in MMF dose and fup its blood level
We never decrease dose of MMF below 2gm through out the whole transplantation except in patient with persistent leucopenia and after exclusion of CMV and do at least once MMF trough level and we keep tac level at high side.
Late(after one year) of stable kidney functions and no events of rejection we also keep MMF at same dose but we decrease other medications to keep it at the minimal levels hoping to be sure that our patient still well covered by MMF specially if tac level get lower at any point by any other drug or food
Also my own reflection obese patients are at more risk of rejection because we never measure MMF and usually underimmune suppressed.
References:
Mycophenolate mofetil (Cellcept) and mycophenolate sodium (Myfortic): Drug information. Lexicomp Online. Copyright © 1978-2021 Lexicomp. (accessed on 9 November 2021
Bentata, Y. (2020). Mycophenolates: The latest modern and potent immunosuppressive drugs in adult kidney transplantation: What we should know about them?. Artificial organs, 44(6), 561-576.
Barry D Kahan 1, Paul Keown, Gary A Levy, Atholl Johnston, Therapeutic drug monitoring of immunosuppressant drugs in clinical practice. 2002 Mar;24(3):330-50
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
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
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
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 a term used for the percentage or the fraction (F) of the administered dose of a drug that reaches the systemic circulation. Bioavailability is practically 100% following intravenous administration but it could be lower for other routs such as oral or dermal. Bioavailability may be influenced by the first pass effect (metabolizing effect of organs through which drug passes before reaching the systemic circulation, properties of dosage forms, and different formulations of a given drug.
Therapeutic equivalence is another term that indicates that drug products when are given to the same patient at the same dosage, provide the same therapeutic and adverse effects. It is especially important for some immunosuppressive drugs such as cyclosporin which have different products. In addition, the difference between its therapeutic and toxic or ineffective concentration is small and considered to have a narrow therapeutic window. Bioavailability is usually assessed by determining the area under the plasma concentration–time curve. The most reliable measure of a drug’s bioavailability is AUC. AUC is directly proportional to the total amount of unchanged drug that reaches systemic circulation.
For example, the bioavailability of microemulsion formulation (Neoral) is better than sandimmune. Bioavailability of oral administered cyclosporin is 30%-45% of intravenous infusion, And sublingual dosing of tacrolimus is one half of that required for the oral administration.
Measuring of the blood level of immunosuppressive agents is utilized for monitoring them. For Neoral cyclosporin, its peak level, typically 2 hours after dosing (C2) may correlate better with drug exposure than its trough level (C0). for Tacrolimus, trough level (drawn immediately preceding the next dose expresses an adequate drug exposure. For mTOR inhibitors, the trough level correlate well with therapeutic effects as well.
For Mycophenolic acid, therapeutic drug monitoring is not routinely performed, and the blood level of Azathioprine is not valuable, because its blood level can’t determine its effectiveness.
Thanks, Esmat for your excellent reply
It would be better to write in your own words.
Thanks All
I acknowledge your hard work and excellent contribution
How many of you working in a transplant unit and measuring MPA levels?
No,It is not measured in our unit only CNIs and mTOR inhibitors
We ve just started measuring them recently
It’s not measured in our country
Immunosuppressant drugs should be closely monitored to achieve the balance state between drugs efficacy and their side effects.
Most clinicians used therapeutic drug monitoring TDM to monitor drug concentration and to avoid adverse effects of these drugs on the transplanted patients.
Overdose (supratherapeutic) concentration make the patient on infection risk due to over immunosuppression while low dose (sub therapeutic) put the patient in a risk of graft loss .
Many factors that affecting level of concentration such as using other drugs (drug interactions) ,sex, infection, liver diseases and renal impairment .
Most common drugs that are used in kidney transplantation and need TDM are : cyclosporine ,mycophenolate mofitile ,tacrolimus and sirolimus .
Drug bioavailability refers to the rate at which the active form of the drug enters the systemic circulation ,it’s determined by dosage and route of administration.
In summary drug bioavailability refers to the rate of active form of the drug reaches the target site of action .
Monitoring of immunosuppressive drugs after kidney transplantation is critical to achieve therapeutic level and avoid drug toxicity .Itis involves both clinical and therapeutic monitoring
1- ATG : clinical monitoring for signs of cytokine release or allergic reaction
As well as monitoring level of CD3 to adjust the dose (not universally agreed).
2- Tacrolimus : through monitoring 12 h through level in serum
3- Cyclosporine through C2 ( serum drug level 2 h after the dose) (1)
Drug bioavailability : define as a measurement of the rate and fraction of the initial drug dose that succeed to reach site of drug action or the body compartment where the drug can be monitored. (2)
1- Holt, D. W. (2002). Therapeutic drug monitoring of immunosuppressive drugs in kidney transplantation. Current opinion in nephrology and hypertension, 11(6), 657-663.
2- Price, G., & Patel, D. A. (2020). Drug Bioavailability.
The calcineurin inhibitors monitored in a meticulous way to ensure the drug level was enough to prevent rejection.
Cyclosporine monitor in two way Cmin which the sample drawn immediately preceding the next dose or C2 when the sample withdrew 2 hours after the dose.
Tactolimus followed by trough level .
The bioavailability mean the concentration of the drug rich the circulation after administration; here it reflect as The area under the curve (AUC).
Monitoring immunosuppressive treatment is through therapeutic drug monitoring.
TDM is used with drugs that have narrow therapeutic index and interpersonal variability .
TDM is very important in transplantation in order to ensure least toxic dose of the drug is used , to maintain efficacy and to reduce side effects
There are two main methods for determination of immunosuppressive drugs in transplant patients: immunoassays and liquid chromatography-based methods (high-performance liquid chromatography (HPLC)
Traditionally most laboratories use immunological methods but Due to cross-reactions with some metabolites of these drugs, overestimation of the concentrations is a major problem in immunological techniques
Ciclosporin :
Whole blood concentration of the drug is used.
Could be measured pre dose ( trough level ) ,or 2hourse after the dose ( C2, C max )
Recent studies have shown that C2 reflects more actual exposure to ciclosporin .
HPLC is considered the gold standard for measuring of ciclosporin levels
Tacrolimus
Whole blood concentration is used.
is recommended that TAC be monitored at 12 hour trough levels ( C0) just before morning dose administration
the relationship between C0 and clinical outcomes is still unclear.
MMF
Trough levels are not widely used although interpersonal variability in pharmacokinetics of MMF
MMF can’t be measured in plasma at any time after oral administration, because they are rapidly metabolized .
Previously no studies have shown that its concentration correlates either to toxicity or rejection, but recently studies showed that there is some relation with clinical outcomes
Sirolimus
The predose concentrations are generally targeted in the range 4-12 μg/l when sirolimus is used with CsA or tacrolimus.
References
Wallemacq P, Armstrong VW, Brunet M, et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference. Ther Drug Monit. 2009 Apr;31(2):139–52. http://dx.doi.org/10.1097/FTD.0b013e318198d092.
Bioavailabilty means the ability of a drug to be absorbed and utilised by the body
cyclosporine
bioavailability after oral dose-30-45%
absorption is increased by food
oral dose- 7mg/kg in 2 divided doses
pediatric dose- as above
iv dose- one third of oral dose infused over 2 hours twice daily.
therapeutic monitoring
AUC is ideal but impractical as multiple blood sample collection involved and complex formulae.
C0 level corelates poorly with AUC- but still widely used .
C2 level correlates better with AUC- target C2 levels cannot be achieved in 20-40% pts,practical difficulty in obtaining accurate samples.
target trough levels post transplantation
0-6 months = 200-250ng/ml
6-12 months= 150-200 ng/ml
>12 months=80 -150 ng/ml
tacrolimus
bioavailability -20%
absorption is decreased by food
oral dose- 0.1-0.2mg/kg in 2 divided doses
pediatric dose- 0.2-0.3 mg/kg in 2 divided doses
iv dose- 0.03-0.05mg/kg as an iv infusion over 24 hrs
therapeutic monitoring
C0 levels correlate well with AUC
target trough levels post transplantation
0-6 months=8-12 ng/ml
6-12 months=6-10 ng/ml
>12 months= 4-8ng/ml
sirolimus
oral dose
loading =6-12 mg( usually 2 -4 times the maintenance dose)
maintenance dose= 2-4mg
iv= not available
therapeutic monitoring
C0 levels correlate with AUC
target levels
0-6 months= 8-12 ng/ml
> 6 months= 6-10 ng/ml
Azathioprine
oral dose= 1.5 – 2mg/kg once daily
iv= 50% of oral dose
therapeutic monitoring
complete blood count initially weekly then monthly,LFT 3 monthly.
mycophenolic acid
oral dose
MMF= 1000mg BD
MPA=720 mg BD
IV dose= 100% oral dose
pediatric dose= 600mg/m2 BD
BIOAVAILABILITY=90%
therapeutic drug monitoring
C0 levels correlate poorly with AUC
there is little compelling evidence to support routine MPA therapeutic monitoring as measuring MPA AUC is complex.
bioavailability
When a medicine is given intravenously, its bioavailability is 100 percent by definition. However, because of intestinal endothelial absorption and first-pass metabolism, a medication’s bioavailability is generally reduced when delivered by methods other than intravenous.
mathematically
bioavailability= AUC for extra vascular formulation/ AUC for intravscular formulation.
Various methods of TDM are available
older immunoassay (IA)-based methods- microparticle enzyme IA (Abbott Diagnostics, Chicago, IL, USA), and enzyme multiplied IA (EMIT, Dade Behring, Glasgow, DE, USA)
they are not so accurate,
there is interference with other substances,
they measure inactive metabolite,
and their limit of detection is not wide.
recent liquid chromatogram (LC) based- liquid chromatogram mass spectroscopy or LC-tandem mass spectroscopy.
costly,
labor intensive, and
require good technical support
Newer IAs
chemiluminescent microparticle IA (Abbott Diagnostics) and Quantitative Microsphere System (QMS™, Thermo-Fisher)
functional sensitivity <1 ng/ml
overcome the disadvantages of older IAs
Several strategies for TDM of Tac
C0
C2
C3
C4
LSS in which instead of using multiple samples,only 2 or 3 samples are taken and AUC calculated.
Therapeutic drug monitoring of tacrolimus in kidney transplantation
Shyam Bihari Bansal
Good
Therapeutic monitoring of the immunosuppression drugs is critical in the management of patients receiving kidney transplantation. As to offer adequate exposure to the drug and to prevent drug toxicity that can even affect graft function.
All drugs except (Mycophenolic acid), are primarily metabolized by the CYP3A system in the liver, and many drugs can induce these enzymes and ultimately affect the immunosuppression drug levels.
There are inter-patients variabilities related to food, drugs use, genetic (whether highly accelerator or not).
The principal approach to the measurement of CNI and Tacrolimus has been and remains immunoassays.
Cyclosporine (CNI):
C0 Sample taken 12 hrs after the previous dose and just before the coming dose.
C2 after 2 hrs from the dose. And comprehensive guideline on the implementation of C2 monitoring has been developed. The rationale for its use comes from that most of the variability in the 12 hr AUC can be explained using the first four hours of the observation curve (AUC 0 – 4) and C2 is a good surrogate for AUC 0 – 4 . also reaching the C2 target concentration early after transplantation has a better effect on graft rejection, whereas the time to reach C0 target values has no apparent impact.
Tacrolimus
Almost all centers depend on C0 measurement. Because it gives a good reflection to AUC.
Tacrolimus is the more effective drug for the prevention of acute rejection.
Sirolimus
There is good correlation between C0 conc and AUC
Target concentrations are lower using the current chromatography assay.
Mycophyenolic acid :
Generally, fixed-dose administration of this drug is used. There is an interest in plasma concentration-guided dosing.
Bioavailability:
Reflect the percent of the drug which reaches circulation after its administration. Intravenous administration has 100% bioavailability.
Reference:
1. Holt DW. Therapeutic drug monitoring of immunosuppressive drugs in kidney transplantation. 2002;
2. Lim MA, Kohli J, Bloom RD. PT SC. Transplant Rev [Internet]. 2016; Available from: http://dx.doi.org/10.1016/j.trre.2016.10.006
therapeutic monitoring of immunosuppression is important to avoid toxicity and maintain adequate immunosuppression
Cyclosporine: monitored using
Tacrolimus: monitored using
Sirolimus:
Everolimus:
Bioavailability: the percentage of administered dose of drug that reach the target site for a defined time to make its therapeutic effect
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. For majority purposes, bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered
**Currie GM. Pharmacology, Part 2: Introduction to Pharmacokinetics. J Nucl Med Technol. 2018 Sep;46(3):221-230. [PubMed]
monitoring immunossupressive drugs
You need to mention and explain the methods used for drug monitoring.
Bioavailability (F) 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-MTOR inhibitors:
Everolimus (Zortress) Oral bioavailability: 30%
*Effect of food in absorption:
High-fat meal: ↓Cmax by 60%; ↓AUC by 16%,Should be taken at a consistent time each day in relation to meals
*Half-life in hours: 30 (19 to 41),Prolonged in hepatic impairment, excreted primarily via feces
Sirolimus (Rapamune): Oral bioavailability: 18% (tablet),14% (oral solution)
*Effect of food in absorption: High-fat meal: ↑AUC by 23 to 35%
Should be taken at a consistent time each day in relation to meals
*Half-life in hours: 62 (46 to 78) Prolonged in hepatic impairment, excreted primarily via feces.
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
Excellent Mohamed
Well done. What is the IV dose in relation to the oral dose?
Prograf 5 mg/ml concentrate for solution for infusion
Oral Prograf therapy should commence at 0.10 – 0.20 mg/kg/day administered as two divided doses
If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous therapy of 0.05 – 0.10 mg/kg/day should be initiated as a continuous 24-hour infusion
SANDIMMUN Concentrate for Solution for Infusion 50mg/ml.
The recommended dose of Sandimmun concentrate for solution for infusion is approximately one-third of the corresponding oral dose
*Patients should be converted from intravenous to oral medication in both medications as soon as individual circumstances permit. Intravenous therapy should not be continued for more than 7 days
Mycophenolate mofetil 500 mg powder for concentrate for solution for infusion
Mycophenolate mofetil for infusion is an alternative dosage form to Mycophenolate mofetil oral forms that may be administered for up to 14 days. The initial dose of Mycophenolate mofetil for infusion
The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose).
Immunosuppressants require therapeutic drug monitoring because of their narrow therapeutic index and significant inter-individual variability in blood concentrations. This variability can be because of factors like drug-nutrient interactions, drug-disease interactions, renal insufficiency, inflammation and infection, gender, age, polymorphism, and liver mass. Drug monitoring is widely practiced especially for cyclosporine, tacrolimus, sirolimus, everolimus, and mycophenolic acid.
Whole-blood trough concentrations of tacrolimus or cyclosporine are routinely monitored among kidney transplant recipients to achieve proper dosing and to avoid over-immunosuppression and drug toxicity. Since the CNI concentration should reflect a 12-hour trough or two-hour post-dose (C2) level, it should first be confirmed that the blood was drawn at the correct timing. Similarly, trough levels of everolimus or sirolimus for patients taking these agents should be measured.
Bioavailability is a term used to describe the percentage (or the fraction (F)) of an administered dose of a drug that reaches the systemic circulation. Different generic brands of the same transplant medications are available in the market. Most of the published reports on bioavailability focused on cyclosporine, followed by tacrolimus and MMF. Different Synthetic cyclosporines are currently approved for use in the United States except for 2 generic formulations of cyclosporine, Equoral ® and Gengraf.
Tsipotis et al, carried a Systematic Review and Meta-Analysis to examine the relative bioavailability of these medications through following the FDA guidance by comparing the rate (C max ) and extent (AUC (0–t) ) of absorption of generic formulations available worldwide relative to their brand counterparts, as well as he examined the efficacy and safety of generic cyclosporine formulations relative to the brand cyclosporine Neoral. He concluded that Generic formulations of cyclosporine, tacrolimus, and MMF met the FDA requirement for bioequivalence against their respective brand counterparts on the basis of the 90% CI of 0.80–1.25 for the T/R drug’s C max and AUC (0–t). However, substantial heterogeneity was observed. In subgroup analyses, the C max achieved by Cicloral ® relative to Neoral ® did not meet the FDA criteria for bioequivalence, raising concerns about its pharmacokinetic profile. In terms of efficacy and safety, generic cyclosporine formulations appeared non-inferior to Neoral in kidney transplant recipients; however, the results were deemed inconclusive due to the wide confidence limits around the effect estimates.
Moreover, a study of incident kidney transplant recipients found that first-year costs were significantly higher in patients receiving generic cyclosporine, compared to those treated with brand cyclosporine, due to dose escalation or addition of another immunosuppressant.
References:
1. Mohammadpour N, Elyasi S, Vahdati N, Mohammadpour AH, Shamsara J. A review on therapeutic drug monitoring of immunosuppressant drugs. Iran J Basic Med Sci. 2011 Nov;14(6):485-98. PMID: 23493821; PMCID: PMC3586862.
2. 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
Many immunosuppressive drugs require measurement of their concentration with subsequent dosage adjustment. This is performed by therapeutic drug monitoring (TDM). The most common immunosuppressants require TDM because of the narrow therapeutic index and significant variability in blood concentration between individuals. Multiple factors contribute to interindividual variabilities like drug-nutrient interactions, drug disease interaction, renal insufficiency, inflammation, infection, age, and gender. In renal transplantation, both supratherapeutic and subtherapeutic drug concentrations can have a devasting result. In At subtherapeutic dose, the patient is at risk of allograft rejection while in the supratherapeutic dose patient may develop drug-specific side effects and infections.
For Examples :
Cyclosporin
It is an acyclic peptide immunosuppressant used to prevent graft rejection and it improving long –term survival of a patient with a renal transplant. Earlier both blood and plasma were used to measure its concentration but now whole blood is used as a matrix for estimation for cyclosporine concentration.. several methods are used to assess cyclosporine, and each differs in specificity for the parent compound. High performance liquid chromatography(HPLC) is the most specific method and consider as the reference method. Its peak level is typically 2 hours (C2) s after dosing better than the trough level.
Tacrolimus
It is an immunosuppressant that has emerged as a valuable therapeutic alternative to cyclosporin. It has a narrow therapeutic window. It is recommended that dosing be guided by routine TDM of whole blood trough concentration.
Mycophenolic Acid
It is an active immunosuppressant metabolite of the prodrug mycophenolate mofetil (MMF). It is effective in reducing the rate of acute rejection.it has large interindividual and intraindividual variability. Plasma is the preferred matrix for MPA measurement. It is mainly bound to albumin .so any change in albumin concentration can affect MPA concentration.
Sirolimus
It is a new macrolide immunosuppressant derived from streptomyce hygroscpicus. It is poorly absorbed from GIT and oral bioavailability 15%. It is monitoring is necessary for successful patient management. Commonly whole blood has been used for trough levels.
These drugs are also monitored by their clinical sides effect.
Bioavailability refers to the extent to which a substance or drug becomes completely available to its intended biological destination. More accurately, it is a measure of the rate and fraction of the initial dose of the drug that successfully reaches either; the site of action or the bodily fluid domain from which the drug,s intended targets have unimpeded access.1,2,3
References:
1.Currie GM. Pharmacology, Part 2: Introduction to Pharmacokinetics. J Nucl Med Technol. 2018 Sep;46(3):221-230. [PubMed]
2.Herkenne C, Alberti I, Naik A, Kalia YN, Mathy FX, Préat V, Guy RH. In vivo methods for the assessment of topical drug bioavailability. Pharm Res. 2008 Jan;25(1):87-103. [PMC free article] [PubMed]
3.Chow SC. Bioavailability and Bioequivalence in Drug Development. Wiley Interdiscip Rev Comput Stat. 2014;6(4):304-312. [PMC free article] [PubMed]
The idea of drug monitoring emerged aiming to reach better benefits from the immunosuppressive medications with less side effects .The fact that immunosuppression itself has many drawbacks being a double edged weapon necessitates close follow up .
There’s a thin line between over and under immunosuppression especially for those drugs with narrow therapeutic index , the success is to protect the kidney and the recipient as well from both rejection , infections (especially in the current COVID epidemic worldwide) and malignancies through therapeutic drug monitoring thus attaining the best level needed for immunosuppression with the least side effects .
Unexpected results from drug levels can occur due to unknown causes may be intraindividual causes ; idiosyncrasy may be a cause . Major events (rejection or infection) can occur even with targeted drug levels !! thus there’s no need to increase the risks more with failing to proper monitoring.
Timing of drug monitoring and frequency of doing so is according to guidelines , depending on the time of transplant , risk factors (desensitization and induction )levels before , changed doses , liver status , kidney status, other medications affecting the levels that may be introduced at any time after the transplant : antihypertensives or antibiotics or antifungals affecting the levels for example .
Tacrolimus has a narrow therapeutic index, trough level should be checked regularly according to guidelines
Cyclosporine trough level and peak level which is more important or more accurate as it correlates more to the AUC
MMF levels are monitored
Evirolimus and sirolimus levels are checked also according to guidelines
Drug bioavailability is defined as the extent at which the active metabolite of the drug enter the systemic circulation and reach the site of action.
Abbott KC, Kimmel PL, Dharnidharka V, et al. New-onset gout after kidney transplantation: incidence, risk factors and implications. Transplantation 2005; 80:1383.
Barry D Kahan 1, Paul Keown, Gary A Levy, Atholl Johnston, Therapeutic drug monitoring of immunosuppressant drugs in clinical practice. 2002 Mar;24(3):330-50;
Osorio JM, Bravo J, Pérez A, et al. Magnesemia in renal transplant recipients: relation with immunosuppression and posttransplant diabetes. Transplant Proc 2010; 42:2910.
Jennifer Le. Drug Bioavailability. MSD mannual professional version. Oct 2020
I will not add much to my colleagues input.
How to monitor immunosuppressive drugs?
1- monitor therapeutic drug level
2- monitor for side effects and adverse reactions even within the therapeutic range.
Bioavailability= AUC for X route of administration / AUC for IV route of administration.
for oral medications, it is affected by GIT absorption, metabolism, hepatic metabolism, endothelial absorption, distribution, and utilisation.
Dear All
What are the bioavailabilities of the following drugs and what are their clinical application?
There is a present for the best answers (an original text of Transplant Immunology).
Immunosuppressive drugs are used to reduce
the immune response in organ transplantation and autoimmune disease. In transplantation, the major classes of immunosuppressive drugs used today are: (1) glucocorticoids, (2) calcineurin inhibitors, (3) antiproliferative/antimetabolic agents, and (4) biologics (antibodies).
These drugs have a high degree of clinical success in treating conditions such as acute immune rejection of organ transplants and severe autoimmune diseases. But also they require lifelong use and nonspecifically suppress the entire immune system, exposing patients to considerably higher risks of adverse effects [1].
A narrow therapeutic index unique to each patient, as well as variable absorption, distribution, and elimination, are characteristics of these drugs. Therapeutic drug monitoring ensures that concentrations are not too high or too low, thereby reducing the risks of toxicity or rejection.
The therapeutic range (therapeutic index) is the ratio between the toxic dose and the therapeutic dose of a drug. The closer this ratio is to 1, the more difficult the drug is to use in clinical practice.
The therapeutic index for immunosuppressant drugs is very low . Clinical use of drugs with a narrow therapeutic index has led to the monitoring of drug concentrations in patients – therapeutic drug monitoring – in which the plasma concentration of a drug is measured and the dose adjusted to achieve a desired therapeutic drug concentration.
a therapeutic range is a range of drug concentrations within which the probability of the desired clinical response is relatively high and the probability of unacceptable toxicity is relatively low [2].
The aim of TDM is to optimize pharmacotherapy by maximizing therapeutic efficacy, while minimizing adverse events, in those instances where the blood concentration of the drug is a better predictor of the desired effect(s) than the dose.
Many factors contribute to the interindividual variability including drug-nutrients interactions, drug-disease interactions, renal insufficiency, inflammation and infection, gender, age, polymorphism and liver mass.
Therapeutic monitoring:
Cyclosporine (CsA)
With the original formulation of CsA, Sandimmune® C0 was the best practice, but during the conversion of patients from that formulation to the improved formulation, Neoral® the 2 h post-dose concentration has been advocated as a single concentration monitoring alternative to C0 [3].
The area under the concentration-time curve for CsA over a 12-hour drug administration interval (AUC0-12h) was a more precise predictor of graft loss and incidence of acute rejection than other parameters, including the C0. Since then, subsequent studies on the pharmacokinetics of CsA in renal transplant patients have identified that intrapatient variability in AUC values over time was directly correlated with the risk of chronic rejection [3].
Tacrolimus (TRL)
The therapeutic range for TRL used by most transplantation centers is 5–20 ng/mL in blood.
TRL whole-blood through concentrations have been found to correlate well with the area under the concentration-time curve measurements in liver, kidney and bone marrow transplant recipients (r= 0.91-0.99). Thus, through concentrations are good index of overall drug exposure, and are currently used for routine monitoring as part of patient care posttransplantation [4].
Therapeutic ranges of TRL after kidney transplantation are reported as a range for various times after transplant: 0-1 month, 15-20 μg/L; 1-3 months, 10-15 μg/L; and more than 3 months, 5-12 μg/L [95]. TRL blood concentrations are monitored 3 to 7 days a week for the first 2 weeks, at least three times for the following 2 weeks, and whenever the patient comes for an outpatient visit thereafter [5].
Mycophenolic acid (MPA)
MPA TDM is currently only used in a few transplant centers on a routine basis, whereas a few others only checked MPA exposure in case of unexpected acute rejection or adverse event or drug interaction. Most of the centers never measure MPA.
Sirolimus (SRL)
Because of the long half-life and extensive tissue distribution of the drug, steady-state concentrations are not reached before day 6 after initiation of therapy or after a dosage change. Thus, daily concentration monitoring is not necessary; the first SRL measurements should not be obtained before day 4 after inception of, or change in therapy. Thereafter, recommend monitoring Cmin,ss weekly for the first month and bi-weekly for the next month, targeting a 5 to 15 μg/L range if CsA is being used concomitantly .
Everolimus (EVL)
EVL is a drug with a narrow therapeutic index.
The recommended therapeutic range for EVL is a trough concentration of 3 to 8 ng/mL.
Reference
1 Krensky AM, Vincenti F, Bennett WM. Immunosuppressants, Tolerogens, and Immunostimulants. In: Brunton L. (ed) Goodman and Gilman’s The Pharmacological Basis of Therapeutics 11th ed. McGraw-Hill Co. New York, NY. 2006.
2 Evans W. General Principles of Clinical Pharmacokinetics. In: Burton ME., Shaw LM., Schentag JJ., Evans WE. (ed) Applied Pharmacokinetics and Pharmacodynamics. Principles of Therapeutic Drug Monitoring. USA: Williams and Wilkins; 2006.
3 Johnston A., Holt DW. Cyclosporine. In: Burton ME., Shaw LM., Schentag JJ., Evans WE. (ed) Applied Pharmacokinetics and Pharmacodynamics. Principles of Therapeutic Drug Monitoring. USA: Williams and Wilkins; 2006.
4Staatz C, Taylor P, Tett S. Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation. Nephrology Dialysis and Transplantation 2001;16(9):1905-9.
5 Scott LJ, McKeage K, Keam SJ, Plosker GL. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003.
6
Bioavailability is that fraction of the administered drug which reaches systemic circulation and reaches site of action.
as we know most of ktrs patients uses triple immunosuppresion in form low dose predinsolone, with antimetabilite either (azathiprine or mmf, and cnis either (cyclosporine or tacrolimus).also mTOR inhibitors like sirolimus and evorlimus are used.
The therapeutic drug level monitoring (TDM) is important because an optimal drug level will help in preventing rejections and avoiding toxicity of the drug causing side-effects.
some drugs like cnis and sirolimus should be mointored according to how far is the pt from tranplantion.
for example
a-Tacrolimus: Trough whole blood levels (sample is taken just before the dose intake, 12 hours post last dose; 24 hours after last dose, if using long acting tacrolimus) correlates well with AUC, especially in first few months post transplant.
b-Cyclosporine: Trough plasma (C0) levels (sample is taken just before the dose intake, 12 hours post last dose) as well as blood levels taken 2 hours after dose (C2 levels) correlate well with AUC.
c-sirolimus and Everolimus: Trough whole blood levels (sample is taken just before the dose intake, 12 hours post last dose)
-The immunosuppressive medicines’ pharmacokinetics are complicated and variable.
–Therapeutic medication monitoring is critical in assisting clinicians in keeping immunosuppressive drug levels in the blood and plasma within therapeutic ranges. Excessive variation in concentrations outside of the narrow therapeutic ranges can have significant clinical consequences. Therapeutic medication monitoring ensures that concentrations are not excessively high or low, lowering the risk of toxicity or rejection.
-cyclosporine, tacrolimus, mycophenolic acid, sirolimus, everolimus, azathioprine, daclizumab and basiliximab, alemtuzumab, and glucocorticoids are some of the immunosuppressive medications.
-Biovalidity is the degree and rate at which the active component (drug or metabolite) enters systemic circulation
-It depends on 3 factors :pharmaceutical factors, patient related factors, route of administration
-Chemical equivalence:
2 or more formulations have the same designated chemical substance in the same amount as an active ingredient.
-Pharmaceutics equivalence:
2 or more formulations are the same in strength,content uniformity, purity,quality , disintegration and dissolution characteristics
Reference
–Piedras, A.L.R., De la O Arciniega, M. and Vázquez, J.R., 2013. Clinical pharmacology and therapeutic drug monitoring of immunosuppressive agents. In Current Issues and Future Direction in Kidney Transplantation. IntechOpen.
The immunosuppressive drugs is monitored to allow the use of lowest dose to prevent rejection and at the same time the side effects to be at minimum.
some drugs needs drug level monitoring , while others need monitoring of adverse effects only.
Bioavailability: is the amount of the drug that reach systemic circulation after it had been ingested by the patient.
What are the types of Lab tools that can be used for TDM? What is the most useful? Why you should know the apparatus used for TDM of CNI?
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%
Bioavailability is defined as the extent of a substance or drug becomes completely available to its intended biological destination. Really the 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 body fluid from which the drug’s intended targets have unimpeded access. Due to purposes a bioavailability is related to the fraction of the active form of a drug that reaches systemic circulation unaltered. This definition achieved 100% of the active drug that enters systemic circulation will successfully reach the target site .Although, it should be appreciated that this definition is not inclusive of drugs that do not require access to systemic circulation for function The bioavailability of these drugs is measured by different parameters discussed elsewhere.
Dear All
What do you call the result of dividing the level of a given drug given orally and the level of the same drug if given intravenously?
Bioavailability
Excellent Amal
>>> Therapeutic drug monitoring :
plays a key role in helping clinicians maintain blood and plasma levels of immunosuppressive drugs within their respective therapeutic ranges.
***Therapeutic drug monitoring (TDM) of immunosuppressive drugs is becoming an increasingly complex matter as the number of compounds and their respective combinations are continuously expanding. Unfortunately, in clinical practice, monitoring predose trough blood concentrations is often not sufficient for guiding optimal long-term dosing of these drugs. The excellent short-term results obtained nowadays in renal transplantation confer a misleading feeling of safety despite the fact that long-term results have not substantially improved, really there’s a point where longer graft survival could counteract the increasing need for transplant organs and less toxicity and side-effects could ameliorate patient survival.
*** Calcineurin inhibitors >>>
Tacrolimus
We must pay attention that predose trough blood tacrolimus concentrations (C0) do not accurately reflect total drug exposure as measured by the 12-h dose interval area under the concentration curve (AUC0−12 h), both in renal and other solid organ transplantation . Especially when C0 is evaluated for its clinically relevant predictive accuracy, by calculating both the prediction error and bias , the usefulness of tacrolimus trough concentrations is questionable. Other clinical studies that repeatedly showed an excellent correlation between tacrolimus C0 and AUC0−12h were often in nonrenal transplantation and failed to examine predictive performance of C0 as suggested .It seems not surprising that every single blood concentration sampling time point is prone to a substantial bias, caused by practical factors such as the exact method and timing of sampling.
Today, few prospective studies can actually demonstrate a clear relationship between tacrolimus exposure which measured as predose trough concentration and clinical efficacy and toxicity.
In additional ,another difficulty with defining useful tacrolimus target concentration ranges is the time dependency of the latter and the changing influence of clinical and biological factors. It is obvious that early after grafting higher immunosuppressive drug concentrations are required in order to prevent rejection while later on during follow-up, chronic drug toxicity becomes an important issue .As a result, early after transplantation, serious side-effects are caused by overimmunosuppression (e.g. infections, PTDM, neurotoxicity).
Cyclosporine :
It’s shown that Mahalati et al. was the first to show prospectively that abbreviated 4-h AUC concentration profiles were superior to C0 with respect to predicting clinical efficacy (prevention of acute rejection) and nephrotoxicity . Abundant other limited sampling strategies for cyclosporin were proposed of which several adequately predicted the full dose-interval AUC and were recently summarized by David and Johnston . The conclusion of the latter review of 38 studies was clear, there is no ‘best’ algorithm for estimating cyclosporin AUC from sparse data.
Mainly for reasons of practical simplicity a new single cyclosporin concentration sampling point was derived form Mahalati’s AUC0−4 data and gave rise to the new concept of C2 monitoring. Although Mahalati et al. found C3 as best predictor of the 12-h dose-interval AUC that correlated with acute rejection and nephrotoxicity during the first week after transplantation , C2 better reflected the time point of maximal pharmacodynamic effect of cyclosporin measured as percentage inhibition of calcineurin and suppression of interleukin-2 release from T cells . The cyclosporin blood concentration 2h post-dosing was relatively easy and accurate to determine with different assays and was the best predictor for the 4-h cyclosporin AUC in subsequent studies .There are a lot of studies in kidney and liver transplantation validated the use of cyclosporin C2 monitoring for prevention of acute rejection and to a lesser extent for reducing calcineurin-inhibitor-induced nephrotoxicity .
It was found that A C2 level ≥1700ng/ml on day 3 post-transplantation had a 92% negative predictive value for acute kidney rejection in the first 6months for recipients without delayed graft function . This minimal C2 threshold was subsequently refined to 1500 ng/ml (on day 7) by the findings of two other studies in renal recipients, one protocol with and the other without induction with monoclonal antibodies against the interleukin-2 receptor .
***Mycophenolate mofetil>>>
The main target involving TDM for MPA are distinct from that of calcineurin inhibitors. It is clear in renal transplantation that predose trough plasma concentrations of MPA do not predict total drug exposure measured as 12-h AUC and that abbreviated 2-h AUC profiles, usually obtained by three concentration sampling points (C0, C30 or C40 and C2), are accurate in predicting total exposure . The free (pharmacologically active) fraction of the drug is determined by allograft dysfunction through alterations in albumin binding and secondary to increased levels of the glucuronide MPA metabolites that are excreted by the kidney , the inactive MPAG-glucuronide and the pharmacologically active Acylglucuronide . The fact that the latter is also implicated in the occurrence of clinically relevant side-effects like diarrhoea and anaemia , further complicates the situation. Finally, the pharmacokinetics of MPA are characterized by a specific postoperative evolution that is mainly determined by the daily dose of the drug and the concomitant calcineurin
inhibitor.
For anaemia we must also consider a relationship with MPA exposure (AUC), like others as well as for leukopenia . Other MMF-associated adverse events like gastrointestinal side-effects were poorly associated with MPA exposure in our study as shown by others .
In order to address at least some of the problems of applying abbreviated MPA AUC measurements in clinical practice, a large international multicentre study in renal transplantation has recently commenced, examining the clinical relevance of concentration-controlled MMF dose adjustments based on abbreviated (2-h) target AUC profiles versus fixed dose treatment. Whether TDM of MMF is advantageous in terms of both efficacy (prevention of acute rejection) and toxicity will be assessed in this trial.
***mTOR inhibitors>>>
There’s no doubts about that TDM is necessary for clinical application of sirolimus in solid organ transplantation .Few studies have demonstrated that, similar to calcineurin inhibitors, mTOR inhibitors are characterized by a narrow therapeutic window, highly variable absorption and large intra- and interindividual variability in pharmacokinetic behaviour . However when sirolimus is used in a low fixed dose of 2mg/day in combination with a full dose cyclosporin (separated by 4h), systematic concentration monitoring can usually be omitted .The latter implies a minimal obtained blood sirolimus trough concentration of 5ng/ml as this shown a clinical threshold differentiating for acute rejection, at least in combination with cyclosporin . Whether long-term association of sirolimus and tacrolimus does not cause alterations of both drug’s blood concentration, remains unclear . Reports showing an effect of a standard dose tacrolimus on maintenance low dose sirolimus imply an interaction .Interestingly, significant decreases in tacrolimus exposure were observed early after transplantation in another report using low doses of sirolimus .
The upper limit of sirolimus exposure, discriminating the onset of adverse events, was determined around 15ng/ml in several studies combining the former with cyclosporin . Especially for thrombocytopenia and hypertriglyceridaemia an exposure–response relationship could be defined. Using receiver operating characteristic curves, an inflection point for thrombocytopenia of 14ng/ml, hypertriglyceridaemia of 11ng/ml and hypercholesterolaemia of 13ng/ml could be determined . With everolimus, a similar exposure–response relationship could be discerned for thrombocytopenia and to a lesser extent for hypertriglyceridaemia and hypercholesterolaemia.
The above data permit us to prudently outline a therapeutic window for sirolimus between 5 and 15g/ml in combination with cyclosporin. However, when cyclosporin is eliminated from this combination higher target levels between 12 and 20ng/ml are advised based on the results of a large multicentre trial examining the feasibility of early calcineurin-inhibitor elimination .As sirolimus seems to induce a different type of allograft nephrotoxicity, distinct from that of calcineurin inhibitors.
### Finally >>>>
~Therapeutic drug monitoring remains the cornerstone of today’s concentration-controlled management of immunosuppressive therapy in renal transplantation. Despite the spectacular evolution in pharmacodynamic research, the progressive unravelling of the individual pharmacogenomic profile and the useful application of drug probes in order to identify drug metabolism, clinicians still have to rely on classic TDM for daily patient care. In recent years it has become clear that abbreviated AUC concentrations are stronger and more reliable predictors of concentration–exposure and exposure–response relationships for the majority of currently used immunosuppressive drugs. Comparative prospective clinical trials are necessary in order to objectively weight the advantages of abbreviated AUC monitoring against classic predose trough concentrations, in terms of cost-effectiveness, feasibility and clinical relevance with regard to long-term patient morbidity and mortality and graft survival. At the same time, it is a challenging task to further refine the therapeutic window for the individual drugs and more importantly for the increasing number of different drug combinations. In order to do so, large prospective observational pharmacokinetic studies are mandatory, carefully examining the relationship between drug exposure and clearly defined efficacy and toxicity endpoints. This relationship has to be studied in a long-term, time-dependent manner in order to recognize important changes in drug (and drug metabolite) pharmacokinetics and identify crucial time points after successful transplantation for optimal use of AUC monitoring.
Thanks, Dr Amal for your effort. I noticed a lot of copying and pasting.
Thanks doctor,
I will avoid copying and pasting.
Routine follow up is recommended to be done by transplant nephrologist in first year then by general nephrologist thereafter since risk of complications decrease after first transplant year.
Routine follow up visits may be done as follow :
⦁ Twice weekly in first month
⦁ Weekly for 1 m
⦁ Every 2 weeks for 1m
Then after first 3 months, monitoring is recommended every 3 m
I- Monitoring whole blood trough level of immunosuppressive drugs (CNI) (1)
a- Tacrolimus T0 (12 h for immediate release and 24 hrs for extended release formulation)
⦁ If rATG is used for induction it is recommended to keep T0 at 7-10 ng/ml in the first month then 3-7 ng/ml thereafter.
⦁ If rATG is not used for induction it is recommended to keep T0 at 8-10 ng/ml in the
b- Cyclosporine C0 (12-hour )
⦁ 200- 300 ng/ml in first 3 months, and 50-150 thereafter
Drug bioavailability :
⦁ Explain the relationship between the dose of drug given and the its level in blood.
⦁ Tacrolimus level may differ in the same patient taking the same dose (intra – patient variability) as food decrease absorption of tacrolimus by 30%.
⦁ Tacrolimus level may differ between patients taking the same dose (inter – patient variability) depending on the activity of cytochrome B450 which differ between renal transplant recipients.
⦁ Patients with higher activity of cytochrome B450 are more prone to have lower level of tacrolimus in blood, and tend to use higher doses of tacrolimus to achieve therapeutic drug level, these patients have higher incidence of rejection and graft loss.
⦁ If the drug level divided by the dose of tacrolimus used was < 1 that mean this patient is fast metabolizer, and need higher doses of tacrolimus.
⦁ Moreover, we have to beer in mind that elderly patients have lesser activity of cytochrome P450 when compared to young and may need lower doses of tacrolimus than young.
II- Monitoring of toxicity of immunosuppressive drugs :
1- Cosmetic problems such as gingival hyperplasia, hirsutism (cyclosporine), alopecia (tacrolimus),
2- HTN, PTDM, hyperlipidemia (2)
⦁ Related to the use of CNI, corticosteroids
⦁ So it is recommended to check for blood glucose with each follow up visit and screen for HBA1c, lipid profile every 3 m for 1 year starting from 3 m post transplant then annually
3- Neurological abnormalities such as tremors (tacrolimus), posterior reversible leukoencephalopathy (tacrolimus, MMF)
4- Infection: all immunosuppressive increase risk of infections, which increase risk of death (3). So it is recommended to screen for the following :
⦁ BK virus using urine and/ or blood test every month for 6 months then /3 m for 2 ys post transplantation.
⦁ CMV by PCR in patients not receiving prophylaxis to be done weekly in first 3 month post transplant, and in patients receiving prophylaxis every 3 m for 1y (R+/D+) or for 2 ys (R-/D+)
5-Malignancy
⦁ Renal transplant recipient have 3 fold increase in risk of malignancy when copared to general population, espicially skin, lip cancers, PTLD, kaposi sarcoma, anogenital cancer and RCC (4)
⦁ Screening of cancer is as general population except for skin cancer which should be done by the patietn every month and by expert dermatologist every year.
6- Renal dysfunction (proteinuria and/or renal imparment )
⦁ May be due to multible causes but when talking in relation to immunosupressive drugs the most common cause of renal dysfunction are overdose of CNI (drug toxicity, viral infection, interstitial nephritis associated with PTLD), or subtherabiotic dose (rejection) or CAN, or may be due to TMA related to CNI
⦁ Also CNI can cause hyperkalemia, hypomagnesimia (5)
⦁ So it is recommended to do creatinine, electrolytes, urine analysis with each follow up visit, and protein- creatinie ratio every 3 m till 1 year post transplant then every 6-12 mounth therafter
⦁ Renal biopsy is indicated if there is allograft dysfunction
7- Hyperuricemia is common with CNI as they decrease excretion of UA In urine. 96)
8- GIT and hepatobiliary side effects especially diarrhea with mycophenolate mophetile can be improved when switching to enteric coated formulation and hepatitis with azathioprine
9- Hematologic side effects including
⦁ Anemia (CNI, azathioprine, MMF)
⦁ Leukopenia (azathioprine, MMF) (7)
⦁ TMA (CNI)
⦁ So it is recommended to monitor CBC with each follow up visit
10- Bone disease
⦁ Osteoporosis due to glucocorticoids, CNIs, persistent hyperparathyroidism may play a rule
⦁ So it is recommended to measure serum ca, p with each fu visit, fu vit D and PTH every 6 m, DEXA scan 3 m post transplant and if there is risk of fracture repeat it every 6-12 m.
III- Monitoring for drug-drug interactions
1- 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.
2- 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.
3- Statin may increase the level of tacrolimus, and increase muscle toxicity with cyclosporine
4- Cyclosporine decrease level of MMF.
5- Allopurinol and febuxistat should not be used with azathioprine.
6- PPI decrease effect of MMF but not EC-MPS.
REFERANCES
1-Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3:S1.
2-Kasiske BL, Guijarro C, Massy ZA, et al. Cardiovascular disease after renal transplantation. J Am Soc Nephrol 1996; 7:158.
3- The AST Infectious Disease Community of Practice, Amercian Society of Transplantation, Infectious Disease Guidelines for Transplantation. Am J Transpl 2009; 9 (Suppl 4):S1.
4- Vajdic CM, McDonald SP, McCredie MR, et al. Cancer incidence before and after kidney transplantation. JAMA 2006; 296:2823.
5- Osorio JM, Bravo J, Pérez A, et al. Magnesemia in renal transplant recipients: relation with immunosuppression and posttransplant diabetes. Transplant Proc 2010; 42:2910.
6- Abbott KC, Kimmel PL, Dharnidharka V, et al. New-onset gout after kidney transplantation: incidence, risk factors and implications. Transplantation 2005; 80:1383.
7- Hartmann EL, Gatesman M, Roskopf-Somerville J, et al. Management of leukopenia in kidney and pancreas transplant recipients. Clin Transplant 2008; 22:822.
Thanks, Sherif
Explain the relationship between the ORAL dose of the drug given and its level in blood if given intravenously.
If we give the same dose of a drug orally and intravenously, the drug level when given intravenously will be higher since it will reach the circulation directly without being affected by gastrointestinal absorption and hepatic first pass.
When the drug is administered IV its bioavalibity is 100%. However when administered by oral route, its bioavalibity is generally lower than IV route due to intestinal absorption and first-pass metabolism.
1-Due to a narrow therapeutic index and large interpatient pharmacokinetic variability, TDM is routinely performed for individualization of the Tac dose to maintain drug efficacy and minimize the consequences of under- and overexposure.
Unfortunately, the evidence for the optimal Tac C0 is more limited than one would expect of a drug so extensively pre-scribed and studied.
Based on the current literature, there is little support to promote a specific therapeutic window. Besides this, the relationship between Tac concentration and either acute rejection or toxicity remains controversial.
Acute cellular rejection episodes occur when the Tac concentration is within the target concentration range and patients having supra-therapeutic exposure sometimes do not suffer from side effects.
This suggests that Tac whole-blood predose concentrations do not always correlate with its pharmacological effect and indicate that novel matrix or monitoring strategies are needed to better predict and monitor the effect of Tac treatment.
Novel options include the measurement of Tac concentrations within the lymphocyte and the unbound concentration. Both options are technically demanding but seem feasible with the recent availability of sophisticated analytical methods.
The intracellular Tac concentration is the most extensively studied option of the two. An association between the Tac concentration and acute rejection has been demonstrated
As Tac is mainly metabolized by CYP3A5, and as it is known that CYP3A5 expressers require a two-fold higher dose to reach the same exposure compared with non-expressers, it seems reasonable to implement preemptive pharmacogenetic testing.
However, two RCTs failed to demonstrate a decreased risk of acute rejection or any other clinical benefit of basing the Tac starting dose on an individual’sCYP3A5 genotype. More sophisticated dosing strategies are needed.
Sirolimus: clinically useful target concentration window (C0: 10–12 ng/ml in the first 6 months post-transplantation and 5–10 ng/ml thereafter),
Downloaded by [Erasmus University] at 06:18 15 December 20
2-Bioavailability is that fraction of the administered drug which reaches systemic circulation. It can be calculated by diving the AUC of the oral drug by AUC of intravenous drug and multiplying by 100
Louise M. Andrews, Yi Li, Brenda C. M. De Winter, Yun-Ying Shi, Carla C.Baan, Teun Van Gelder & Dennis A. Hesselink (2017) Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients, Expert Opinion on DrugMetabolism & Toxicology, 13:12, 1225-1236, DOI: 10.1080/17425255.2017.1395413
Flechner SM, Goldfarb D, Modlin C, et al. Kidney transplantation without calcineurin-inhibitor drugs: a prospective, randomised trial of sirolimus versus cyclosporine. Transplantation 2002; 74: 1070. Louise M. Andrews, Yi Li, Brenda C. M. De Winter, Yun-Ying Shi, Carla C.
Baan, Teun Van Gelder & Dennis A. Hesselink (2017) Pharmacokinetic considerations related to
therapeutic drug monitoring of tacrolimus in kidney transplant patients, Expert Opinion on Drug
Metabolism & Toxicology, 13:12, 1225-1236, DOI:
10.1080/17425255.2017.1395413
As some immunosuppressive drugs has narrow therapeutic window e.g Tacrolimus and cyclosporine, their blood level should be regularly detected to avoid either toxicity or graft rejection.
The protocol of monitoring depend on the point of time since transplantation , with close and more frequent monitoring is used during early days post transplantation, and regular monthly then quarterly monitoring later on.
Bioavailability of the drug mean the ability of the drug or its active metabolit to reach blood stream (systemic circulation)
Monitoring of immunosuppressant drugs with drug trogh level (not exceed it) and kept in its therapeutic level according to time of the transplanted graft
Monitoring of immunosuppressive drugs after kidney transplantation is critical to achieve therapeutic level and avoid drug toxicity .Itis involves both clinical and therapeutic monitoring
1- ATG : clinical monitoring for signs of cytokine release or allergic reaction
As well as monitoring level of CD3 to adjust the dose (not universally agreed).
2- Tacrolimus : through monitoring 12 h through level in serum
3- Cyclosporine through C2 ( serum drug level 2 h after the dose) (1)
Drug bioavailability : define as a measurement of the rate and fraction of the initial drug dose that succeed to reach site of drug action or the body compartment where the drug can be monitored. (2)
1- Holt, D. W. (2002). Therapeutic drug monitoring of immunosuppressive drugs in kidney transplantation. Current opinion in nephrology and hypertension, 11(6), 657-663.
2- Price, G., & Patel, D. A. (2020). Drug Bioavailability.
How do you monitor the immunosuppression drugs?
Immunosuppressive therapy in renal transplant patients is the cornerstone to avoid rejection. Immunosuppression drugs have narrow therapeutic levels above which toxicity may occur, with a risk of rejection if dose is reduced or levels are not in the therapeutic targets.
Maintenance immunosuppressive therapy included CNI, antimetabolite, steroids and mTORi.
For calcineurin inhibitors, patients treated with tacrolimus, we monitor whole-blood 12- and 24-hour trough (C0) concentrations for the immediate-release and extended-release preparations, respectively. C0 target levels adepends on the initial induction therapy:
In patients who receive antilymphocyte-depleting:
-7 to 10 ng/mL for the first month after transplantation
-3 to 7 ng/mL for subsequent months
In patients who do not receive antilymphocyte-depleting agents for induction therapy:
-8 to 10 ng/mL for months 1 to 3 after transplantation
-3 to 7 ng/mL for subsequent months
In most patients treated with cyclosporine, we monitor whole-blood 12-hour trough (C0) concentrations. With this approach, our C0 target levels are the following:
-200 to 300 ng/mL in months 1 to 3 after transplantation
-50 to 150 ng/mL for subsequent months
Patients on CNI may develop toxicity even in the narrow therapeutic level, so side effects and toxicity should be monitored. If patients are unable to tolerate these agents due to toxicity or other adverse effects, alternative immunosuppression drugs should be considered involving the use of mTOR inhibitors or belatacept.
For mTORi, in particular Everolimus, the recommended therapeutic range is a trough concentration of 3 to 8 ng/mL. For Sirolimus the therapeutic target is 5 to 15 μg/L.
For antimetabolic agents, we do not obtain target or trough levels now, since they are not routinely available, reliable, or associated with efficacy or toxicity.
For the Dosing of glucocorticoids, there is no consensus on the optimal dose or maintenance schedule of glucocorticoids following kidney transplantation but the target is to reach the least effective dose and in some protocols to stop steroids. We don’t measure steroids level but we monitor side effects of the immunosuppressive therapy including steroids.
What is meant by “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.
bioavailability is a term in pharmacology, meaning the percentage of the amount of a specific drug reaching the blood circulation after a certain time of intake of that drug.
immunosuppressive drugs can be monitored by :
1- clinical signs of side effects and toxicity, e.g tremors for CNI, GIT symptoms as diarrhea for MMF, cushinoid features of steroids,…. etc
2- serum levels of drugs as trough levels of CNI.
3- histopathology feaures of toxicity as CNI toxicity.
Immunosuppressive management is an art in managing renal transplant patients. It is a balance between providing adequate immunosuppression to achieve desired clinical effects to reduce the risk of rejection without exposing the patient to their toxic side effects .
Immunosuppressive medications has narrow therapeutic window and both intra and inter pharmacokinetic variability. Accordingly, therapeutic drug monitoring (TDM) for these agents is essential by measurement of drugs and/or their breakdown products (metabolites) at timed intervals to maintain a relatively constant concentration of the medication in the blood and to limit sub and supra therapeutic drug exposure and concurrent risk for graft rejection and toxicity.
Examples of monitored drugs:
Cyclosporine: monitoring of C2 after the dosing is more sensitive predictor of the outcome than trough C0 monitoring. However, C0 levels are more widely used
Tacrolimus: C0 is used in clinical practice, 12 hr trough concentration for immediate release preparation and 24 hr trough concentration for extended release preparation. however, the relation between C0 and AUC(area under the curve varied between clinical trials)
Mycophenolic acid: concentration is not correlated with drug exposure or outcome
Sirolimus and Everolimus: Trough whole blood levels ,the sample is taken just before the dose intake, 12 hours post last dose.
Bioavailability is defined as the ability of a drug to be absorbed at utilized by the body(enter the circulation and reaches the site of its action)
· Jennifer Le , Drug Bioavailability .MSD Manual professional version .Oct 2020
· Up to date. cited on 7th Nov. 2021
· Handbook of Kidney Transplantation, Danovitch. 6th edition
Close monitoring of CNI is pivotal in the management of renal transplant recipients because the response & metabolism differs from patient to another. Also there is a close relation between blood level of drug & organ rejection or toxicity.
During monitoring of Cyclosporine ( sandimmun) trough level used ( C min) but in monitoring of Neoral usually use peak level (C2) because it correlate better with drug exposure than trough level.
Tacrolimus level usually monitoring by measuring trough level ( immediately before next dose).
Sirolimus has long half life, so drug level monitoring done after several days of dose adjustments & once the drug level became stable, frequent monitoring not required.
Bioavailability: referred to both the amount & the rate of drug absorption. The amount of absorbed drug referred to the portion of the drug that reach to blood stream in active form.Bioavailability of oral drugs affected by physical & chemical factors which in turn affect the absorption. These factors include gastrointestinal mucous membrane, GI transient time, & first bypass &/ or excretion by bowel or liver.
References:
Monitoring of the Immunosuppression drugs:
Microsampling is Important in Therapeutic Drug Monitoring:
Just a few decades ago, conventional techniques such as Venous Blood Sampling were used to obtain plasma or serum samples for TDM. With the invention of dried blood sampling, clinicians can enjoy a simple and convenient sampling method.
DBS(dried blood spot) sampling involves taking blood samples with a small finger prick using an automatic lancet. With the right setup, the right equipment, and adequate training, this can allow remote patient monitoring.
Immunosuppression that need TDM include:
Bioavailability:
Definition:Bioavailability refers to the extent a substance or drug becomes completely available to its intended biological destination(s).
Simply :The degree to which or rate at which a drug or other substance is absorbed or becomes available at the site of physiological activity after administration.
Excellent
Yes, “the degree to which or the rate at which a drug or other substance is absorbed or becomes available at the site of physiological activity after administration”.
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.(1)
Immune suppressive drugs monitoring
1-drugs doses
2-patient compliance
3-drugs interaction like with other immune suppression drugs ,antibiotics ,anticonvulsant
4-side effects of drugs (history and examination)
5-serum drug level
6-in calcinurine inhibitors need renal function test and s.electrolytes
7-in MMF,AZA need CBP
8-in M-TOR inhibitors need GUE for proteinurea
Reference
By Jennifer Le, PharmD, MAS, BCPS-ID, FIDSA, FCCP, FCSHP, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego
Last full review/revision Oct 2020| Content last modified Oct 2020
Bioavailability: the proportion of a drug administered by any non vascular route that gain access to the systemic circulation.1
we monitor the immunosuppressive drugs through therapeutic drug level monitoring.
for CNI:
1.Tacrolimus: 12 hr trough concentration ( C0) for immediate release preparation & 24 hr trough concentration for extended release preparation.
target levels for those who receive ATG for induction:
7-10 ng/ml for the first month after transplantation
3-7 ng/ml for subsequent months
target for those who do not receive ATG for induction:
8-10 ng/ml for 1-3 months post transplant
3-7 ng/ml for subsequent months.
2.cyclosporine:
in most patients monitoring of C0 level has been done
target levels:
200-300 ng/ml in 1-3 months post transplantation
50-150 ng/ml for subsequent months
poor correlation between clinical outcome and drug exposure noticed by measuring C0 level, thus in some patients( poor absorption of cyclosporine), monitoring of C2 level is required( 2 hr.s post drug exposure).
target levels:
800-1000 ng/ml in the 1-3 months post transplantation
400-600 ng/ml in the subsequent months
antimetabolites:
Azathioprine, MMF : no tests done since they are not routinely available, reliable or associated with toxicity.
mTOR inhibitors
sirolimus if used with cyclosporine and prednisolone trough level of 5-15 ng/ml associated with protection from rejection
if used with azathioprine and prednisolone drug level of 30 ng/ml needed in the first 2 months post transplant reduced to 15 ng/ml thereafter.
Everolimus: 3-8 ng/ml trough concentration is needed.2
References:
Monitoring of the immunosuppressive therapy is essential part of kidney transplantation. This exercise is to ensure that the desired drug level is obtained and the patient is not over-immunosuppressed(=toxicity) and under-immunosuppressed(=rejection). Example of drug monitoring ;
1.Calcineurin inhibitor ; Tacrolimus is monitored best by trough level (C=0) , measuring the level before the next dose, 12 h or 24h after the last dose. Initially 8 to 12 ng/ml is desired tac level , after 6 months level of 6.3 to 8 max , but this is centre dependent. Cyclosporine is measured by both C = 0 and C2 which is the measurement 2 h after the dose .Usual level is in the range of 150 to 200 ng/ml and it is centre dependent
2.mTORi ; e.g. Everolimus / Sirolimus , the level of Everolimus range from 3 to 8 ng/ml depending whether it is used with CNI minimization protocol or elimination
3.Antiproliferative e.g. MPA, or Azathioprine. Measuring the level is not yet standard of practice
Bioavailability refers to the amount drug that research systemic circulation and site of the action after administration.
The aim of Therapeutic Drug Monitoring is to optimize pharmacotherapy by maximizing therapeutic efficacy, while minimizing adverse events.
Cyclosporine
A prospective study showed that although C0 (trough concentration) levels of CsA correlated poorly with dose, Cmax was significantly correlated with dose, Area Under the Curve (AUC) and elimination half-life (t1/2). the 2 h post-dose concentration has been advocated as a single concentration monitoring alternative to C0.
Currently, most transplant centers measure a single steady-state CsA concentration as either a C0 predose trough or 2 hours postdose, while some conduct multiple measurements to determine CsA AUC estimates .
Tacrolimus
Drug levels are obtained as predose (12 hours after previous dose) trough concentrations in whole blood . These trough levels correlate well with area under the curve representing an accurate measure of drug exposure
Mycophenolic acid (MPA)
With trough concentration, plasma concentration of MPA is measured immediately before a dose, and only requires single simple possible association between C0 and decreased rejection in transplant recipients. On the otjer hand timing may not be accurate. Timing may vary from the “ideal” (12 h after last dose) by several hours.
Sirolimus (SRL)
the first measurements should not be taken before day 4 after inception of, or change in therapy.It is recommended to monitor Cmin,ss weekly for the first month and twice weekly for the next month, targeting a 5 to 15 μg/L range if CsA is being also used at Cmin,ss concentrations of 75 to 150 μg/L.
Everolimus (EVL)
It has narrow therapeutic index. The EVL Cmin is a good marker of EVL exposure (AUC), and correlates with pharmacological response and clinical outcomes.
The recommended therapeutic range for EVL is a trough concentration of 3 to 8 ng/mL, because concentrations over 3 ng/mL have been associated with a decreased incidence of rejection, and concentrations >8 ng/mL with increased toxicity.
Reference:
Ana Luisa Robles Piedras, Minarda De la O Arciniega and Josefina Reynoso Vázquez (February 13th 2013). Clinical Pharmacology and Therapeutic Drug Monitoring of Immunosuppressive Agents, Current Issues and Future Direction in Kidney Transplantation, Thomas Rath, IntechOpen,
DOI: 10.5772/54910. Available from: https://www.intechopen.com/chapters/42876
Bioavailability refers to the extent and rate by which the active moiety (drug or metabolite) enters systemic circulation, where it access it’s site of action.
It is 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 have clinical importance; therefore, knowing whether drug formulations are equivalent is essential.
Reference
Jennifer Le , Drug Bioavailability .MSD Mannual professional version .Oct 2020
Just a correction
It is ug/ml NOT ug/L
Dear All
Can you get me a simple and easy-to-understand definition of bioavailability?
Another question regarding C2 for CYCLOSPORINE monitoring, how popular is it and is it better than C0?Is it used in monitoring Tacrolimus?
With SANDIMMUNE, trough levels were used for TDM as it was found that C0 levels correlated better with toxic complications. But with NEORAL, C2 levels corerlated better with drug effects due to better consistent absorption. But for the sake of uniformity, majority of the centers use trough levels.
For tacrolimus, C0 levels are the ones which are usually done, C2 levels have not been shown to be superior to C0 tacrolimus levels. (1)
Although some studies have shown that C2 tacrolimus levels are beneficial as a predictor of acute rejection. (2)
1) Jorgensen K, Povlsen J, Madsen S, et al. c2 (2-h) levels are not superior to trough levels as estimates of the area under the curve in tacrolimus-treated renal transplant patients. Nephrol Dial Transplant 2002.;17:1487-90.
2) Scholten EM, Cremers SCLM, Shoemaker RC, et al. AUC guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients. Kidney Int 2005;67:2440-2447.
as regard cyclosporin C0 is popular than C2, but recently C2 monitoring is found to have better impact on graft survival especially in the 1st 6 months post transplant
E Nemati , B Einollahi, S Taheri, M Moghani-Lankarani, E Kalantar, N Simforoosh, M Nafar, A R Saadat. Cyclosporine trough (C0) and 2-hour postdose (C2) levels: which one is a predictor of graft loss?. Transplant Proc. 2007 May;39(4):1223-4.
as regard tacrolimus has very narrow therapeutic index , in the clinical practice, trough level used routinely , also post dose can be used.
Bernhard Banasa, Bernhard K, .Krämer b, Bernd Krügerb, Nassim Kamarc, Nasrullah Undred.Long-Term Kidney Transplant Outcomes: Role of Prolonged-Release Tacrolimus. Transplantation Proceedings. (52) 1, January–February 2020, P 102-110.
Monitoring of C0 is more common in practice, more popular and more convenient to the patient, but some patients have poor absorption of the drug and thus C2 will correlate better with clinical outcome.
It was found that higher C2 is associated with lower rate of acute rejection (1)
Target C0 800-1000 in first 3 m then 400-600 thereafter
It is not used for tacrolimus
REFERANCES
1- Schiff J, Cole E, Cantarovich M. Therapeutic monitoring of calcineurin inhibitors for the nephrologist. Clin J Am Soc Nephrol 2007; 2:374.
Cyclosporin C2, but not C0, was found to be predictive of long-term graft survival in the first 6 months after transplantation.
C0 is more used than C2. C2 monitoring correlates with better graft survival in the first 6 months post-Tx. C0 is used for monitoring Tacrolimus and not C2.
Bioavailability of a drug in simple language would be the portion of the drug which becomes completely available to its intended destination, that is the systemic circulation
The bioavailability is the amount of drug reaching the general circulation from the delivery system being used. The bioavailability of a drug administered by the intravenous route is 100%.
bioavilability of the drug:
defined as the extent and the rate at which the active metabolite of the drug enter the systemic circulation and reach the site of action.
Bioavailability describe the fraction of a drug given that reach the blood
Excellent Sherif as ever
in relation to what?
Bioavailability is the per cent of the metabolically active substance that reaches the target site of action in relation to the total amount of drug given to the patient (1, 2).
It is the outcome of the pharmacokinetics of the drug (absorption, distribution, metabolism, and elimination). All of which affect the drug’s effect by altering the drug’s concentration at its site of action.
References:
1) Currie GM. Pharmacology, Part 2: Introduction to Pharmacokinetics. J Nucl Med Technol. 2018 Sep;46(3):221-230.
2) Herkenne C, Alberti I, Naik A, Kalia YN, Mathy FX, Préat V, Guy RH. In vivo methods for the assessment of topical drug bioavailability. Pharm Res. 2008 Jan;25(1):87-103.
bioavailability of the drug
The degree and rate at which the drug’s active metabolite enters the systemic circulation and reaches the site of action.
F = AUC for X route of administration ÷ AUC for IV administration
F= bioavailability
Do you think we need a regular check of MPA? What are the risks of high MPA level?
Do you think we need a regular check of MPA?
Mycophenolic acid (MPA) trough levels are poorly correlated with AUC and are not recommended (1).
What are the risks of high MPA level?
There is some studies that suggest a relationship between the degree of mycophenolate exposure (eg, dose, total mycophenolate AUC, free mycophenolate AUC, metabolite(s) AUC, trough concentrations) and the development of bone marrow suppression (most commonly anaemia or leukopenia).
References:
1) Mycophenolate mofetil (Cellcept) and mycophenolate sodium (Myfortic): Drug information. Lexicomp Online. Copyright © 1978-2021 Lexicomp. (accessed on 9 November 2021).
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
TDM of MPA is not usually done although it is important to avoid risk of toxicity, get levels according to immunological risk and posttransplant period and to be balanced with tacrolimus level “high tacrolimus target probably need to be counterbalanced by low target MPA”
high MPA levels increase the risk of over immunosuppression which increase risk of infections and malignancy (not caused by calcineurin inhibitors only)
Bentata, Y. (2020). Mycophenolates: The latest modern and potent immunosuppressive drugs in adult kidney transplantation: What we should know about them?. Artificial organs, 44(6), 561-576.
MPA monitoring is not yet standard of care according to last European Renal Practice guideline. High MPA is associated with GIT upsets, in particular diarrhoea , myelosuppression. some reports of neurotoxicity in Japan. Plus increase risk of infections. Diarrhoea is common reason for discontinuation of MPA and this is associated with increase risk of rejection