Population Pharmacokinetic/Pharmacodynamic Modeling of Tacrolimus in Renal Transplant Recipients: Impact of CYP3A5 Genotype and Wuzhi Capsule Co-Medication

Abstract

Object: Tacrolimus is a crucial immunosuppressant used to prevent renal transplant rejection. While, long-term application of tacrolimus can lead to several adverse reactions that worsen patient prognosis, such as posttransplantation diabetes mellitus and renal injury. This study developed population pharmacokinetic/pharmacodynamic (PK/PD) models from clinical data to investigate the relationships between tacrolimus dose, exposure, and adverse effects in renal transplant recipients. Methods: Demographics, the CYP3A5 genotype, laboratory results, and co-medications were tested as covariates, and dose simulations were performed based on the final models. The population PK model was described by a one-compartment model with first-order elimination and a fixed absorption rate. The CYP3A5 genotype, Wuzhi (WZ) capsule, and postoperative days were significant covariates of tacrolimus clearance. Fasting plasma glucose (FPG) and estimated glomerular filtration rate (eGFR) were characterized by the trough concentration (C0) of tacrolimus in a PK/linear model and maximal inhibitory effect, respectively. Age significantly influenced the baseline FPG and eGFR. The initial eGFR was strongly affected by hemoglobin. Results: The simulations revealed that patients with CYP3A5*1 treated without WZ capsule, for whom no less than 3 mg q12 h as the initial dose was needed, whereas patients with CYP3A5*3/*3 combined with WZ capsule might experience kidney damage even if the dose is 2 mg q12 h; thus, patients with the CYP3A5*3/*3 genotype combined with WZ capsule are not recommended. Conclusion: The population PK/PD models quantified the relationships between tacrolimus dose, exposure, and adverse effects in renal transplant patients, which could serve as a reference for optimizing the individualized dosage of tacrolimus.