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Competing Interests: M.J.E. is employed by Takeda Pharmaceuticals and serves in a consultant/advisory board role for Hansa BioPharma, Veloxis Pharmaceuticals, and BioMatrix Specialty Pharmacy. In the last 24 months, M.J.E. has received grant funding for research from Bristol-Myers Squibb, Veloxis Pharmaceuticals, Octapharma, and CSL Behring. M.J.E. is also the inventor of Wellavive. R.RA. serves as a consultant for MedPace and Sanofi Genzyme. R.R.A. serves as a speaker for Veloxis Pharmaceuticals and Sanofi Genzyme. In the last 24 months, R.R.A. has received grant funding for research funding from Bristol-Meyers Squibb, Veloxis Pharmaceuticals, Hookipa, and Novartis. T.v.G. has received lecture fees and study grants from Chiesi and Astellas and consulting fees from Roche Diagnostics, Vitaeris, Astellas, Aurinia Pharma, and Novartis. The other authors declare no conflicts of interest.

Abstract: When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Recipients of solid organs such as the kidney and heart are treated with standard immunosuppressive regimens, and personalized medicine has not yet reached the clinic for this patient population. Biomarkers potentially will allow treatment regimens to be adjusted, according to the needs of the individual patient. Biomarkers may reflect the degree of immunosuppression of the immune system, or they may reflect early damage to the transplanted organ., (© 2017 The British Pharmacological Society.)

The immunosuppressants cyclosporine, tacrolimus, sirolimus, everolimus, and probably also mycophenolic acid require therapeutic drug monitoring (TDM)-guided dosing to ensure that blood concentrations are kept within the target range in transplant patients. Reliable, accurate, and precise test methods are therefore essential to effectively monitor levels and to make proper dose adjustments. Data from proficiency testing programs have shown substantial interlaboratory variability. Only few attempts have been made to study the underlying causes. The aim of this study was to systematically document current practices used for immunosuppressant drug TDM in clinical laboratories and identify methodological and practice differences, which may cause the variability observed among laboratories. Data collection was primarily conducted by a structured Web-based survey. Invitations to participate in the survey were distributed to clinical laboratories providing immunosuppressant drug TDM. Surveys were completed by 76 laboratories in 14 countries. The results of our survey suggest that there are 3 main reasons for interlaboratory variability: (1) lack of standardization of laboratory procedures and workflows starting with sample collection and handling, (2) lack of use of appropriate reference materials (eg, isotope-labeled internal standards for liquid chromatography-tandem mass spectroscopy), and (3) poor compliance with internationally accepted good laboratory practice guidelines (eg, related to quality control, quality assurance, validation, training of personnel). The results of the survey also suggest that interlaboratory variability is a multifactorial problem. Technical-level consensus on laboratory operational procedures, quality systems, and personnel training will be of great importance to improve quality and interlaboratory comparability.

Generic immunosuppressive drugs are available in Europe, Canada, and the United States. Between countries, there are large differences in the market penetration of generic drugs in general, and for immunosuppressive drugs in particular. The registration criteria for generic immunosuppressive drugs are often criticized. However, it is unlikely that the criteria for registration of narrow therapeutic index drugs are going to change, and bioequivalence studies, performed in healthy volunteers, will remain the backbone of the registration process. It would be good if the registration authorities would demand that all generic variants of an innovator drug have the same pill appearance to reduce errors and promote drug adherence.To allow for safe substitution, a number of criteria need to be fulfilled. Generic substitution should not be taken out of the hands of the treating physicians. Generic substitution can only be done safely if initiated by the prescriber, and in well-informed and prepared patients. Payers should refrain from forcing pharmacists to dispense generic drugs in patients on maintenance treatment with innovator drug. Instead, together with transplant societies, they should design guidelines on how to implement generic immunosuppressive drugs into clinical practice. Substitutions must be followed by control visits to check if the patient is taking the medication correctly and if drug exposure remains stable. Inadvertent, uncontrolled substitutions from 1 generic to another, initiated outside the scope of the prescriber, must be avoided as they are unsafe. Repetitive subsequent generic substitutions result in minimal additional cost savings and have an inherent risk of medication errors.

Introduction: Starting doses of tacrolimus and ciclosporin are typically chosen on a calculated mg/kg bodyweight basis. After initiation of treatment, doses are adjusted with therapeutic drug monitoring (TDM). This trial-and-error approach has been accepted by most physicians and pharmacists involved in the care of transplanted patients., Areas Covered: Dosing algorithms have only fairly recently been proposed to better individualize the starting dose. This review provides an overview of all the currently available dosing algorithms in adult and children for the starting dose of ciclosporin, tacrolimus and mycophenolic acid. In these algorithms, multiple other covariates influencing the starting dose, such as age, hematocrit, comedication and genotype are taken into account. After selecting the starting dose with an algorithm and after initiation of treatment, TDM will, however, remain necessary. Whether or not implementation of such algorithms will improve clinical outcome remains to be demonstrated., Expert Opinion: First of all an algorithm needs to be validated, against an independent dataset. Second, in a prospective study the algorithm should prove to reduce the time to reach the target concentration, and to reduce the number of patients with drug concentrations (far) outside the therapeutic window. Finally, a clinical trial demonstrating a benefit on clinical outcome will be crucial in achieving broad acceptance of calculating starting dose using individualized dosing algorithms.

The transplantation literature includes numerous papers that report associations between polymorphisms in genes encoding metabolizing enzymes and drug transporters, and pharmacokinetic data on immunosuppressive drugs. Most of these studies are retrospective in design, and although a substantial number report significant associations, pharmacogenetic tests are hardly used in clinical practice. One of the reasons for this poor implementation is the current lack of evidence of improved clinical outcome with pharmacogenetic testing. Furthermore, with efficient therapeutic drug monitoring it is possible to rapidly correct for the effect of genotypic deviations on pharmacokinetics, thereby decreasing the utility of genotype-based dosing. The future of pharmacogenetics will be in treatment models in which patient characteristics are combined with data on polymorphisms in multiple genes. These models should focus on pharmacodynamic parameters, variations in the expression of drug transporter proteins, and predictors of toxicity. Such models will provide more information than the relatively small candidate gene studies performed so far. For implementation of these models into clinical practice, linkage of genotype data to medication prescription systems within electronic health records will be crucial.

This overview describes the full spectrum of current pre-clinical and clinical kidney-, liver-, heart- and lung transplantation research performed in Erasmus MC - University Medical Centre in Rotterdam, The Netherlands. An update is provided on the development of a large living donor kidney transplantation program and on optimization of kidney allocation, including the implementation of a domino kidney-donation program. Our current research efforts to optimize immunosuppressive regimens and find novel targets for immunosuppressive therapy, our recent studies on prevention of ischemia-reperfusion-induced graft injury, our newest findings on stimulation of tissue regeneration, our novel approaches to prevent rejection and viral infection, and our latest insights in the regulation of allograft rejection, are summarized., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Implementation of pharmacogenetics in transplantation medicine has not met the expectations expressed 15 years ago. Numerous studies have reported associations between gene polymorphisms and pharmacokinetics of immunosuppressive drugs. Evidence that genotype-based dosing improves outcome is lacking. Extensive therapeutic drug monitoring (TDM) can rapidly correct for the variability in drug exposure caused by genetic differences. The contribution of genotype-based dosing will be more pronounced for drugs for which pharmacokinetic or pharmacodynamic monitoring is not applied.

The calcineurin inhibitor tacrolimus is the backbone of immunosuppressive drug therapy after solid organ transplantation. Tacrolimus is effective in preventing acute rejection but has considerable toxicity and displays marked inter-individual variability in its pharmacokinetics and pharmacodynamics. The genetic basis of these phenomena is reviewed here. With regard to its pharmacokinetic variability, a single nucleotide polymorphism (SNP) in cytochrome P450 (CYP) 3A5 (6986A>G) has been consistently associated with tacrolimus dose requirement. Patients expressing CYP3A5 (those carrying the A nucleotide, defined as the *1 allele) have a dose requirement that is around 50 % higher than non-expressers (those homozygous for the G nucleotide, defined as the *3 allele). A randomised controlled study in kidney transplant recipients has demonstrated that a CYP3A5 genotype-based approach to tacrolimus dosing leads to more patients reaching the target concentration early after transplantation. However, no improvement of clinical outcomes (rejection incidence, toxicity) was observed, which may have been the result of the design of this particular study. In addition to CYP3A5 genotype, other genetic variants may also contribute to the variability in tacrolimus pharmacokinetics. Among these, the CYP3A4*22 and POR*28 SNPs are the most promising. Individuals carrying the CYP3A4*22 T-variant allele have a lower tacrolimus dose requirement than individuals with the CYP3A4*22 CC genotype and this effect appears to be independent of CYP3A5 genotype status. Individuals carrying the POR*28 T-variant allele have a higher tacrolimus dose requirement than POR*28 CC homozygotes but this association was only found in CYP3A5-expressing individuals. Other, less well-defined SNPs have been inconsistently associated with tacrolimus dose requirement. It is envisaged that in the future, algorithms incorporating clinical, demographic and genetic variables will be developed that will aid clinicians with the determination of the tacrolimus starting dose for an individual transplant recipient. Such an approach may limit early tacrolimus under-exposure and toxicity. With regard to tacrolimus pharmacodynamics, no strong genotype-phenotype relationships have been identified. Certain SNPs associate with rejection risk but these observations await replication. Likewise, the genetic basis of tacrolimus-induced toxicity remains unclarified. SNPs in the genes encoding for the drug transporter ABCB1 and the CYP3A enzymes may relate to chronic nephrotoxicity but findings have been inconsistent. No genetic markers reliably predict new-onset diabetes mellitus after transplantation, hypertension or neurotoxicity. The CYP3A5*1 SNP is currently the most promising biomarker for tailoring tacrolimus treatment. However, before CYP3A5 genotyping is incorporated into the routine clinical care of transplant recipients, prospective clinical trials are needed to determine whether such a strategy improves patient outcomes. The role of pharmacogenetics in tacrolimus pharmacodynamics should be explored further by the study of intra-lymphocyte and tissue tacrolimus concentrations.

Unlabelled: This article summarizes part of a consensus meeting about mycophenolate (MPA) therapeutic drug monitoring held in Rome under the auspices of The Transplantation Society in November 2008 (Clin J Am Soc Nephrol. 2010;5:341-358). This part of the meeting focused on the clinical pharmacokinetics of MPA and included discussion on how to measure MPA (active drug) exposure and the differences between the currently available formulations., Summary Points: Because of variability in the dose-concentration relationship, MPA exposure should be measured and doses should be adjusted accordingly to achieve optimal clinical outcomes. Suggested therapeutic exposures derived for MPA from mycophenolate mofetil (MMF) may differ to those that could be useful for MPA from enteric-coated mycophenolate sodium (EC-MPS), particularly if limited sampling strategies or single concentration, especially trough concentrations, is used, as the concentration-time profiles of MPA from the 2 formulations are quite different. The 2 MPA formulations cannot be considered as bioequivalent. The area under the concentration-time curve (AUC 0-12) is considered the criterion standard for monitoring of MPA, which is a reflection of exposure to the drug over the entire dosing period. If a limited sampling protocol coupled with multilinear regression or Bayesian estimation is used to estimate this parameter, it should be used only for the population in which the model has been developed and should preferably include at least one time point after 4 hours (preferably around 8 or 9 hours after MMF dosing). If a single time point is to be used as a surrogate for an AUC 0-12, trough concentration of MPA may be the most practical but, from a pharmacokinetic standpoint, is not the most informative time point to choose. Because limited sampling strategies to estimate MPA exposure from EC-MPS have not yet been well developed and fully evaluated, nor have accurate Bayesian estimators been reported, AUC 0-12 measurement is still necessary to obtain reliable estimates of MPA exposure in patients treated with EC-MPS. The measurement of MPA trough concentrations should not be used at all for MPA exposure assessment following administration of EC-MPS. Because limited sampling strategies to estimate MPA exposure from EC-MPS have not yet been well developed and fully evaluated, nor have accurate Bayesian estimators been reported, AUC 0-12 measurement is still necessary to obtain reliable estimates of MPA exposure in patients treated with EC-MPS. The measurement of MPA trough concentrations should not be used at all for MPA exposure assessment following administration of EC-MPS. Lower (or higher) than expected total MPA exposure in patients with severe renal impairment may still indicate sufficient free MPA exposure. Mycophenolate free exposure measurement/estimation is likely to be beneficial in patients with severe renal impairment (creatinine clearance b25 mL/min) to guide dosage estimation, especially because renal function changes over time after transplant, while recognizing that robust prospective studies to show the clinical advantage of measuring free MPA exposure are still required. Lower total measured MPA exposure in patients with hypoalbuminemia may still indicate sufficient free MPA exposure. Mycophenolate free concentration measurement and estimation of exposure are likely to be beneficial in patients with a serum albumin less than or equal to 31 g/L to guide interpretation of MPA exposure. A 1.5-g twice-daily starting dose of MMF rather than a 1-g twice-daily starting dose of MMF is more likely to achieve the minimum target MPA exposure in adult transplant recipients receiving concomitant cyclosporine therapy. Because the cyclosporine dose is progressively tapered following transplantation, MPA exposure should be measured repeatedly and MMF should be doses adjusted accordingly to achieve optimal clinical outcome. Mycophenolate exposure should be measured in the first week after transplant, then each week for the first month, each month until month 3, and subsequently every 3 months up to 1 year with appropriate dosage adjustment, as AUC is likely to increase over time. After 1 year, if dosage requirement has stabilized, MPA exposure can be assessed each time the immunosuppressive regimen is changed or a potentially interacting drug is introduced or withdrawn. Assessment of UGT1A9 single nucleotide polymorphisms (-275TNA, -2152CNT, -440CNT, -331TNC) should be considered before transplantation to assist in dosing decisions to achieve optimal MPA exposure immediately after transplant. Consideration of the points summarized above should lead to more effective dosage adjustment based on sound applied pharmacokinetic and pharmacodynamic principles., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A roundtable meeting to discuss the use of therapeutic drug monitoring (TDM) to guide immunosuppression with mycophenolate mofetil was held in New York in December 2004. Existing recommendations for the initial months after transplantation were updated. After ensuring adequate levels of mycophenolic acid (MPA, the active metabolite of mycophenolate mofetil) immediately after transplantation, optimal efficacy may require only a few dose adjustments, because intrapatient variability in exposure seems low. Recommendations based on current knowledge were made for posttransplantation sampling time points and for target MPA concentrations. Algorithms for estimating MPA exposure using limited sampling strategies were presented, and a new assay for MPA discussed. It was agreed that because of interpatient variability and the influence of concomitant immunosuppressants, TDM might help optimize outcomes, especially in patients at higher risk of rejection. The value of TDM in the general transplant population will be assessed from large, ongoing, randomized studies.

Cyclosporin has greatly improved the short and medium-term outcomes for solid organ transplantation. However, the effect on the long-term outcome has been less impressive. This can partly be attributed to the side effects of cyclosporin, and partly to the fact that the use of cyclosporin has not led to a reduced incidence of chronic allograft nephropathy. Efforts to minimise these side effects have led to the development of the microemulsion form of cyclosporin and improved methods for therapeutic drug monitoring (dosage based on blood levels instead of body weight). Finally, the introduction of new immunosuppressive drugs has made it possible to further reduce the dose of cyclosporin; this might eventually lead to cyclosporin-free immunosuppressive regimens.

Within the field of solid organ transplantation there is an unprecedented interest in therapeutic drug monitoring of immunosuppressive drugs. Ideally therapeutic drug monitoring should cost-effectively lead to improved efficacy of the drug and to a reduction in side effects. Therapeutic drug monitoring will be most effective if there is a large interpatient variability and a small intrapatient variability. Therapeutic drug monitoring in transplantation is largely based on correlations between drug concentrations and toxicity or between drug concentrations and efficacy. Pharmacodynamic monitoring of immunosuppressive drugs has not reached the stage of widespread clinical application. In part this is caused by the fact that most of the pharmacodynamic assays are time-consuming, costly and in some cases only give a result after several days of incubation. Another reason for the limited interest in pharmacodynamic monitoring is the lack of data showing improved outcome if dose adjustment is based on pharmacodynamics rather than pharmacokinetics. On the other hand, such data are also lacking for pharmacokinetic monitoring. Prospective investigations on the contribution of therapeutic drug monitoring may result in further improvement of the safety and efficacy of our immunosuppressive regimens and more refined methods for therapeutic drug monitoring. There is no contest between pharmacokinetic and pharmacodynamic monitoring. Most likely the results of both ways of monitoring will be complementary.