Abstract
Purpose
Mycophenolate mofetil (MMF), a prodrug of the immunosuppressive agent mycophenolic acid (MPA), is widely used for prophylaxis of solid organ transplant rejection. MPA is primarily metabolized to 7-O-mycophenolic acid glucuronide (MPAG), an inactive metabolite that undergoes enterohepatic recirculation (EHC). This study assessed ethnic differences in the pharmacokinetics (PK) of MPA and MPAG between healthy Chinese and Caucasian subjects using population PK analysis.
Methods
Data were pooled from 132 healthy subjects (80 Chinese, 52 Caucasians) in eight clinical studies in which MMF was administered in a single oral dose. Population PK analysis was performed using NONMEM®.
Results
The PK of MPA and MPAG were best described by a five-chain compartment model, including a gallbladder compartment for EHC and a transit absorption model. Ethnicity was significantly correlated with the apparent clearance (CL/F) and volume of distribution (V/F) of MPAG but not those of MPA. Weight was identified as a covariate and was correlated with the PK of MPA and MPAG. MPA CL/F was 11.5 L/h for a 70-kg healthy subject, and the MPAG CL/F values were 1.36 and 1.90 L/h for 70-kg Chinese and Caucasian individuals, respectively. Internal and external evaluation indicated model validity.
Conclusions
This is the first population PK analysis to evaluate ethnic differences in the PK of MPA and MPAG in healthy Chinese and Caucasian subjects. No differences were observed in the PK of MPA between healthy Chinese and Caucasian subjects. Although, the MPAG CL/F was approximately 40 % higher in Caucasians, this finding may not be clinically relevant.
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Acknowledgments
The authors sincerely thank Dr. Bing Shen of the First Shanghai People’s Hospital (Shanghai, China) and Dr. Qi Pei of the Third Xiangya Hospital (Changsha, China) for providing their original pharmacokinetic datasets. The authors would also like to thank Dr. Nicolas Frey and Dr. Yuyan Jin of Roche, Ltd. for their invaluable comments. The help of Mr. Lixuan Qian of the Pharmacy School of Fudan University in preparing the manuscript is also appreciated. This project was partially supported by the National Natural Science Foundation of China (No. 81072702) and the Major Research and Development Project of Innovative Drugs, China Ministry of Science and Technology (2012ZX09303004-001).
Conflict of interest
Dr. Jun Shi and Dr. Qiudi Jiang are employees of the Roche Innovation Center Shanghai, China
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Ling, J., Shi, J., Jiang, Q. et al. Population pharmacokinetics of mycophenolic acid and its main glucuronide metabolite: a comparison between healthy Chinese and Caucasian subjects receiving mycophenolate mofetil. Eur J Clin Pharmacol 71, 95–106 (2015). https://doi.org/10.1007/s00228-014-1771-1
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DOI: https://doi.org/10.1007/s00228-014-1771-1