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Pharmacokinetics, limited sampling strategies, and pharmacogenetics of mycophenolic acid in thoracic transplant recipients Ting, Lillian S.L.

Abstract

Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil, is an immunosuppressive agent known to exhibit wide inter-patient pharmacokinetic variability. The metabolism and transport of MPA and the phenolic (MPAG) and acyl (AcMPAG) glucuronides are mediated by UDP-glucuronosyltransferases (UGTs) and multidrug resistance-associated protein 2 (MRP2/ABCC2), respectively. Increasing evidence supports monitoring MPA area-under-the-concentration-time-curve; however, it is impractical and costly to implement. The objectives of this clinical study were to characterize MPA pharmacokinetics, develop MPA limited sampling strategies for estimating MPA exposure, and assess contribution of UGT and ABCC2 genetics to MPA pharmacokinetics and clinical outcomes in thoracic transplant recipients. Seventy thoracic (36 lung, 34 heart) transplant recipients were recruited. Eleven blood samples were obtained over a 12-hour dosing period at steady state. Plasma concentrations of MPA, MPAG, AcMPAG, and free MPA were measured by a high performance liquid chromatography-ultraviolet detection method, and conventional dose-normalized pharmacokinetic parameters were determined via non-compartmental methods. Limited sampling strategies were developed in 64 subjects by stepwise multiple regression analysis using the index group data, and tested in the validation group to determine bias and precision. Genetic polymorphisms in UGT and ABCC2 were determined by sequencing and their contributions to pharmacokinetic variability were investigated in 68 thoracic transplant recipients using multivariate analysis. Significantly lower MPA pharmacokinetic exposure was observed in lung transplant recipients (compared with heart), and in patients taking cyclosporine (compared with tacrolimus). There was wide inter-patient variability of MPA, MPAG and AcMPAG pharmacokinetics. The best limited sampling strategies for both transplant populations were developed from the lung transplant group data; equations (Log C1.5, C2) and (Log C0, Log C1.5) were the best candidates for the heart and lung transplant population, respectively. For both transplant groups, UGT2B7 variants 802T (*2a) and -138A (*2g) were associated with increased AcMPAG AUC (~3-fold) and AcMPAG/MPA (~10-fold) in multivariate analyses, respectively, and high AcMPAG exposure and metabolic ratio were associated with poor clinical outcomes. UGT2B7 is a promising gene candidate that may influence MPA pharmacokinetics clinically; however, larger clinical pharmacogenetic studies in thoracic transplant subpopulations are warranted to corroborate the role of AcMPAG and UGT2B7 variants in optimizing mycophenolate therapy.

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