CYP3A4 and CYP3A5 Polymorphism Effects on Tacrolimus Pharmacokinetics in Chinese Adult Renal Transplant Recipients: A Population Pharmacokinetic Analysis

ZUO Xiaocong; Chee M. Ng; Jeffrey S.Barrett; LUO Aijing; ZHANG Bikui; DENG Chenhui; XI Lanyan; CHENG Ke; MING Yingzi; YANG Guoping; PEI Qi; ZHU Lijun; YUAN Hong; LIAO Haiqiang; DING Junjie; WU Di; ZHOU Yanan; JING Ningning; HUANG Zhijun

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CYP3A4 and CYP3A5 Polymorphism Effects on Tacrolimus Pharmacokinetics in Chinese Adult Renal Transplant Recipients: A Population Pharmacokinetic Analysis

ZUO Xiaocong 1,Chee M. Ng 2,Jeffrey S.Barrett 2,LUO Aijing 3,ZHANG Bikui 4,DENG Chenhui 5,XI Lanyan 4,CHENG Ke 6,MING Yingzi 6,YANG Guoping 4,PEI Qi 4,ZHU Lijun 6,YUAN Hong 4 *,LIAO Haiqiang 4,DING Junjie 7,WU Di 2,ZHOU Yanan 4,JING Ningning 4,HUANG Zhijun 4

1.Clinical Pharmacy and Pharmacology Research Institute, The Third Xiangya Hospital of Central South University, Changsha 410013

2.Laboratory for Applied PK/PD, Clinical Pharmacology & Therapeutics Division, The Children’s Hospital of Philadelphia, Philadelphia 19019

3.Key Laboratory of Medical Information Research in Hunan Higher Education,Changsha 410013

4.Clinical Pharmacy and Pharmacology Research Institute, The Third Xiangya Hospital of Central South University,Changsha 410013

5.State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100083

6.Department of Transplantation, The Third Xiangya Hospital of Central South University, Changsha 410013

7.Department of Pharmacy, Children’s Hospital of Fudan University, Shanghai 200000

*Correspondence author

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Funding: International Scientific and Technological Cooperation Project of Hunan （No.No. 2010WK2006）, National Natural Science Foundation of China （No.No.81102512）, Doctoral Fund of Ministry of Education of China （No.No.20110162120023）, National Basic Research Program of China （No.No. 2011CB512001）

Opened online: 2 May 2013

Accepted by: none

Citation: ZUO Xiaocong,Chee M. Ng,Jeffrey S.Barrett.CYP3A4 and CYP3A5 Polymorphism Effects on Tacrolimus Pharmacokinetics in Chinese Adult Renal Transplant Recipients: A Population Pharmacokinetic Analysis[OL]. [ 2 May 2013] http://en.paper.edu.cn/en_releasepaper/content/4530503

Objective Tacrolimus is used clinically for long-term treatment of antirejection of transplanted organs in liver and kidney transplant recipients though dose optimization is poorly managed. The goal of this study was to investigate the association between tacrolimus pharmacokinetic variability and CYP3A4 and CYP3A5 genotype by a population pharmacokinetic analysis based on routine drug monitoring data in adult renal transplantation recipients. Methods Trough tacrolimus concentrations were obtained from 161 adult kidney transplant recipients post-transplantation. The population pharmacokinetic analysis was performed using the nonlinear mixed-effect modeling software NONMEM version 7.2. The CYP3A4*1G and CYP3A5*3 genetic polymorphisms from studied patients were determined by direct sequencing using a validated automated genetic analyzer. Results A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. Covariates including CYP3A5*3 and CYP3A4*1G alleles and hematocrit were retained in the final model. The apparent clearance of tacrolimus was about 2-fold higher in kidney transplant patients with CYP3A5*3 and CYP3A4*1G higher enzymatic activity (with the CYP3A5 *1/*1 or *1/*3 and CYP3A4*1/*1G or CYP3A4*1G/*1G) compared to those with lower enzymatic activity (CYP3A5 *3/*3 and CYP3A4*1/*1). Conclusion This is the first study to extensively investigate the effect of CYP3A4*1G and CYP3A5*3 genetic polymorphisms and hematocrit value on tacrolimus pharmacokinetics in renal transplantation recipients. The findings suggest that CYP3A5*3 and CYP3A4*1G polymorphisms and hematocrit are determinant factor in the apparent clearance of tacrolimus. The initial dose design is mainly based on CYP3A5 and CYP3A4 genotypes as well as hematocrit.This results may also be good for the maintenance tacrolimus dose optimization and help to avoid fluctuating tacrolimus levels and improve the efficacy and tolerability of tacrolimus in kidney transplant recipients.

Keywords:CYP3A5*3; CYP3A4*1G; hematocrit; population pharmacokinetics; tacrolimus; kidney transplantation

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