New insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid: possible consequences for therapeutic drug monitoring in solid organ transplantation.
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.
de Jonge
Hylke
H
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
Naesens
Maarten
M
Kuypers
Dirk R J
DR
D019703:Calcineurin / Q000494:pharmacology; D065095:Calcineurin Inhibitors; D016903:Drug Monitoring; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D006084:Graft Rejection / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D009173:Mycophenolic Acid / Q000493:pharmacokinetics* / Q000494:pharmacology; D016377:Organ Transplantation / Q000502:physiology*; D016559:Tacrolimus / Q000493:pharmacokinetics*; D014184:Transplantation, Homologous / Q000379:methods / Q000473:pathology
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D019703:Calcineurin; D009173:Mycophenolic Acid; D016559:Tacrolimus