The population pharmacokinetics of sirolimus and CYP3A5*3 polymorphism in Chinese renal transplant patients

Objectives: Sirolimus (SRL) is a widely used immunosuppressive agent in preventing allograft rejection after solid organ transplantation. In this study we established a population pharmacokinetic (PPK) model for SRL in Chinese renal transplant patients, and elucidated the influence of CYP3A5*3 genotypes on SRL PPK parameters and SRL dosing regimen in Chinese renal transplant recipients. Methods: 108 renal transplant patients were enrolled retrospectively. The trough concentration (C0) of SRL in steady state was monitored and pathophysiological data were recorded. The CYP3A5*3 genotypes was determined for each patients. The NONMEM software was used to establish the PPK model for SRL. The influence of age, gender, body weight (BW), renal and liver function, CYP3A5*3 genotype on PPK parameters was evaluated. Results: 915 C0 were obtained from 108 patients. The average C0 was 6.09 ± 3.27 ng/ml. There were 11, 36, 61 patients with CYP3A5*1/*1, *1/*3 and *3/*3 genotype. Single compartment model was the most suitable model in Chinese renal transplant patients. The CL/F, Vd/F and Ka were 10.9 ± 0.99 L/h, 357 ± 102 L and 2.20 l/h. BW (P<0.01), albumin level (P<0.01) and CYP3A5*3 genotype (P<0.01) were found to have significant influence on CL/F of SRL. By using Bayesian method, dosage of SRL to reach the target concentration for CYP3A5*1/*1, *1/*3 and *3/*3 patients were predicted as 2.23:1.77:1. Conclusion: The PPK model established can be used to estimate individualized SRL pharmacokinetic parameters. On the basis of TDM data of SRL, patients pathophysiological data and CYP3A5 genotype, the initial and maintain dosage of SRL in Chinese renal transplant patient can be simulated and individualized immunosuppressive regimen can be designed.