Influence of Donor–Recipient CYP3A4/5 Genotypes, Age and Fluconazole on Tacrolimus Pharmacokinetics in Pediatric Liver Transplantation: A Population Approach

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AIM: To characterize the effect of donor and recipient CYP3A4, CYP3A5 and ABCB1 genotypes as well as relevant patient characteristics on tacrolimus pharmacokinetics in pediatric liver transplantation. PATIENTS & METHODS: Data from 114 pediatric liver transplant recipients were retrospectively collected during the first 3 months following transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling, including characterization of influential covariates. RESULTS: A two-compartment model with first order elimination best fitted the data. Estimates of apparent volume of the central compartment, intestinal clearance, hepatic clearance and intercompartmental clearance were 79 l, 0.01 l/h, 10.9 l/h and 105 l/h, respectively. Time post-transplantation, recipient age, donor CYP3A5 and CYP3A4 genotypes and fluconazole administration significantly influenced tacrolimus apparent clearance while bodyweight influenced volume of distribution. CONCLUSION: The proposed model displayed acceptable fitting performances and enabled identification of statistically significant and clinically relevant covariates on tacrolimus pharmacokinetics in the early pediatric post liver transplantation period.