New Insights Into the Pharmacokinetics and Pharmacodynamics of the Calcineurin Inhibitors and Mycophenolic Acid: Possible Consequences for Therapeutic Drug Monitoring in Solid Organ Transplantation

Abstract

Although therapeutic drug monitoring (TDM) of immunosuppressive drugs has been an integral part of routine clinical practice in solid organ transplantation for many years, ongoing research in the field of immunosuppressive drug metabolism, pharmacokinetics, pharmacogenetics, pharmacodynamics, and clinical TDM keeps yielding new insights that might have future clinical implications. In this review, the authors will highlight some of these new insights for the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus and the antimetabolite mycophenolic acid (MPA) and will discuss the possible consequences. For CNIs, important relevant lessons for TDM can be learned from the results of 2 recently published large CNI minimization trials. Furthermore, because acute rejection and drug-related adverse events do occur despite routine application of CNI TDM, alternative approaches to better predict the dose-concentration-response relationship in the individual patient are being explored. Monitoring of CNI concentrations in lymphocytes and other tissues, determination of CNI metabolites, and CNI pharmacogenetics and pharmacodynamics are in their infancy but have the potential to become useful additions to conventional CNI TDM. Although MPA is usually administered at a fixed dose, there is a rationale for MPA TDM, and this is substantiated by the increasing knowledge of the many nongenetic and genetic factors contributing to the interindividual and intraindividual variability in MPA pharmacokinetics. However, recent, large, randomized clinical trials investigating the clinical utility of MPA TDM have reported conflicting data. Therefore, alternative pharmacokinetic (ie, MPA free fraction and metabolites) and pharmacodynamic approaches to better predict drug efficacy and toxicity are being explored. Finally, for MPA and tacrolimus, novel formulations have become available. For MPA, the differences in pharmacokinetic behavior between the old and the novel formulation will have implications for TDM, whereas for tacrolimus, this probably will not to be the case.

Tacrolimus-Associated Posterior Reversible Encephalopathy Syndrome after Solid Organ Transplantation

“…It was reported that patients carrying at least 1 CYP3A5*1 allele have a lower TAC concentration to dose ratio when compared with nonexpressors (CYP3A5*3/*3) in kidney, liver, lung, and heart transplant recipients [62]; it is obvious that individual pharmacogenetics could affect whole blood TAC concentrations and, consequently, increasing TAC concentrations may lead to an increase in drug-related adverse effects [63]. These preliminary results explained the interindividual variability of neurotoxicity at a genetic level and, furthermore, indicated that genetic polymorphisms might be useful to predict the susceptibility of a patient with an increased risk for TAC-related neurotoxicity rather than a pure concentration-based approach [64]. In this high-risk group for undesirable TAC complications, choosing a different immunosuppressive protocol or aiming at a lower threshold for stopping TAC might eventually allow to reduce the incidence of TAC-associated PRES and improve clinical outcome [64].…”

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

“…Due to a narrow therapeutic index and its large interpatient and intrapatient pharmacokinetic variability, therapeutic drug monitoring (TDM) is routinely performed for individualization of the Tac dose to maintain drug efficacy and minimize the consequences of overexposure [18]. As allografts are nowadays rarely lost as a consequence of acute rejection, adverse events associated with long-term immunosuppression have become increasingly evident [19].…”

Counterpoint: Is Pharmacokinetic or Pharmacodynamic Monitoring of Calcineurin Inhibition Therapy Necessary?

“…Preliminary data suggest that in the early posttransplantation period, CsA intracellular concentrations or AUC 0 -12h in peripheral blood mononuclear cells (PBMC) would be lower in patients experiencing acute rejection or would decrease during the week preceding the acute rejection episode, and that TAC concentrations in PBMC would exhibit a very high interindividual variability (7 ). However, at the present time, the extemporaneous isolation of PBMC from whole blood is laborious.…”

“…However, the determination of tissue CNI concentrations is unlikely to make its way into clinical practice (7 ).…”