Influences of Donor and Recipient Gene Polymorphisms on Tacrolimus Dosing and Pharmacokinetics in Asian Liver Transplant Patients

Abstract

Background: Tacrolimus pharmacokinetics has large inter-individual variability. Objectives: This study aimed to investigate the impact of donor and recipient gene polymorphisms on tacrolimus dosing and pharmacokinetics in Asian liver transplant patients. Methods: Steady-statetacrolimus concentrations at 0, 1, 2, 4 and 6 h were measured. Pharma- cokinetic parameters were estimated with a one-compartment linear model using WinNonlin 6.1 program. DNA from donor liver and recipient blood samples were genotyped for CYP3Aand ABCB1 polymorphisms. Results: A total of 13 donors and 17 recipients were included. Donor genotypes influenced tacrolimus trough concentration-to-dose (C0/D) ratio only at Week 1. Patients with liver grafts from CYP3A5 expressors (*1*1 and *1*3) achieved lower mean C0/D ratio than those with grafts from non-expressors (*3*3) (64.48 versus 129.21 (mcg/L)/(mg/kg/day), P = 0.040). Hence, the dose required to achieve target concentration in patients with donor genotype CYP3A5 expressors was higher than non-expressors (0.12 versus 0.08 mg/kg, P = 0.045). Recipient with ABCB1-C3435T genotype TT demonstrated higher apparent oral clearance of tacrolimus as compared to genotype CC (17.7 versus7.9 L/h, P = 0.033). Conclusions: Donor liver CYP3Apolymorphism could potentially affect tacrolimus C0/D ratio as early as the first week post liver transplant. Genotyping of liver donors may be useful to achieve the optimal drug concentration during this critical period.