CYP3A5 Genotype-Dependent Drug-Drug Interaction Between Tacrolimus and Nifedipine in Chinese Renal Transplant Patients.

Yilei Yang,Xin Huang,Wei Zhao,Jianning Wang,Lequn Su,Yinping Shi,Yan Li,Yi Zheng,Guoxiang Hao,Haiyan Shi,Rui Yang,Xinmei Yang

doi:10.3389/fphar.2021.692922

Abstract

Purpose: The drug-drug interactions (DDIs) of tacrolimus greatly contributed to pharmacokinetic variability. Nifedipine, frequently prescribed for hypertension, is a competitive CYP3A5 inhibitor which can inhibit tacrolimus metabolism. The objective of this study was to investigate whether CYP3A5 genotype could influence tacrolimus-nifedipine DDI in Chinese renal transplant patients. Method: All renal transplant patients were divided into CYP3A5*3/*3 homozygotes (group I) and CYP3A5*1 allele carriers (CYP3A5*1/*1 + CYP3A5*1/*3) (group II). Each group was subdivided into patients taking tacrolimus co-administered with nifedipine (CONF) and that administrated with tacrolimus alone (Controls). Tacrolimus trough concentrations (C0) were measured using high performance liquid chromatography. A retrospective analysis compared tacrolimus dose (D)-corrected trough concentrations (C0) (C0/D) between CONF and Controls in group I and II, respectively. At the same time, a multivariate line regression analysis was made to evaluate the effect of variates on C0/D. Results: In this study, a significant DDI between tacrolimus and nifedipine with respect to the CYP3A5*3 polymorphism was confirmed. In group I (n = 43), the C0/D of CONF was significantly higher than in Controls [225.2 ± 66.3 vs. 155.1 ± 34.6 ng/ml/(mg/kg); p = 0.002]. However, this difference was not detected in group II (n = 27) (p = 0.216). The co-administrated nifedipine and CYP3A5*3/*3 homozygotes significantly increased tacrolimus concentrations in multivariate line regression analysis. Discussion: A CYP3A5 genotype-dependent DDI was found between tacrolimus and nifedipine. Therefore, personalized therapy accounting for CYP3A5 genotype detection as well as therapeutic drug monitoring are necessary for renal transplant patients when treating with tacrolimus and nifedipine.

Highlights

In recent years, modern transplant surgery techniques, immunosuppressants, and donor organ preservation technologies have greatly promoted the development of renal transplantation
This study aimed to assess whether the drug-drug interaction (DDI) between tacrolimus and nifedipine is associated with CYP3A5 genotype in renal transplant recipients
The relatively balanced distribution frequency of CYP3A5 in this study indicate that the CYP3A5*3 allele mutation is less common in Chinese than Caucasians, which facilitates to compare the effects of DDI between tacrolimus and nifedipine (Chakkera et al, 2013; Qu et al, 2017)

Summary

Introduction

Modern transplant surgery techniques, immunosuppressants, and donor organ preservation technologies have greatly promoted the development of renal transplantation. Renal transplantation has become a standard treatment for end-stage renal failure, as it significantly improves patients’ quality of life (Viklicky et al, 2020). Tacrolimus, a calcineurin inhibitor, is one of the most widely used immunosuppressants for solid organ transplants (Staatz and Tett, 2018). Its clinical application is limited by significant differences in treatment response among patients and a narrow therapeutic window (Rong et al, 2019). Tacrolimus is metabolized by the CYP3A subfamily, which mainly includes CYP3A4 and CYP3A5 (Zhu et al, 2015; Yu et al, 2018). Drugs that affect CYP3A4/5 enzyme activity can affect tacrolimus metabolism and concentration

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