PS 08-28 THE EFFECT OF CYP3A4 AND CYP3A5 POLYMORPHISMS ON THE TACROLIMUS PLASMA CONCENTRATION IN CHINESE POST RENAL TRANSPLANT RECIPIENTS

Abstract

Objective: The purpose of this study was to identify the proportion of CYP3A4 and CYP3A5 gene polymorphisms in Chinese renal transplant recipients, and to study the effect of CYP3A4 and CYP3A5 gene polymorphisms on Concentration/Dose(C0/D) of tacrolimus, and to further develop a population pharmacokinetics model for tacrolimus in Chinese renal transplant recipients. Design and Method: 110 recipients with post renal transplant hypertension were genotyped for CYP3A4*1G and CYP3A5*3 using polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP). 70 recipients received tacrolimus at least 1 week and tacrolimus trough levels(C0) were determined. The population pharmacokinetics model, based on tacrolimus plasma concentrations of 188 renal transplant patients, was established using the nonlinear mixed-effect modeling software. Results: We genotyped 110 recipients for CYP3A4 (47.27% CYP3A4*1/*1; 48.18% CYP3A4*1*1G and 4.55% CYP3A4*1G*1G) and CYP3A5 (5.45% CYP3A5*1/*1; 50.00% CYP3A5*1/*3 and 44.55% CYP3A5*3/*3). Among the 70 recipients with post renal transplant hypertension, patients with CYP3A4*1*1 showed a significantly higher C0/D compared with the CYP3A4*1*1G and CYP3A4*1G*1G group (p < 0.05); While the C0/D of CYP3A5*3*3 group was significantly higher than the CYP3A5*1*1 and CYP3A5*1*3 group (p < 0.05). A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. In the final model, clearance (CL/F), distribution volume (Vd/F) and Ka was 30.1L h-1, 3420L and 3.09h-1 respectively. And the CYP3A5*3, hemoglobin and direct bilirubin had significant effect on CL/F, and postoperative days (POD) showed significant influence on Vd/F. Conclusions: Most patients carried the wild allele CYP3A4*1 (G20230A) and the mutant allele CYP3A5*3 (A6986G). The C0/D of tacrolimus was well associated with the CYP3A4*1G and CYP3A5*3 polymorphism. The population pharmacokinetics findings suggest that CYP3A5*3 polymorphisms, hemoglobin and direct bilirubin are determinant factors in the apparent clearance of tacrolimus.