Population pharmacokinetics of mycophenolic acid and its main glucuronide metabolite: a comparison between healthy Chinese and Caucasian subjects receiving mycophenolate mofetil

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• 作者：Jing Ling ; Jun Shi ; Qiudi Jiang ; Zheng Jiao
• 关键词：Mycophenolic acid ; Ethnic differences ; Population pharmacokinetics ; Enterohepatic circulation
• 刊名：European Journal of Clinical Pharmacology
• 出版年：2015
• 出版时间：January 2015
• 年：2015
• 卷：71
• 期：1
• 页码：95-106
• 全文大小：919 KB
• 参考文献：1. USRDS (2013) Annual data report: Atlas of chronic kidney disease and end-stage renal disease in the United States, (2013) National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. http://www.usrds.org/2013/pdf/v2_ch7_13.pdf. Accessed 7 Oct 2014
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  14. Geng F, Jiao Z, Dao YJ, Qiu XY, Ding JJ, Shi XJ, Li ZD, Zhong MK (2012) The association of the UGT1A8, SLCO1B3 and ABCC2/ABCG2 genetic polymorphisms with the pharmacokinetics of mycophenolic acid and its phenolic glucuronide metabolite in Chinese individuals. Clin Chim Acta Int J Clin Chem 413(7-):683-90. doi:10.1016/j.cca.2011.12.003
  15. Jiao Z, Zhong JY, Zhang M,
• 作者单位：Jing Ling (1)
  Jun Shi (2)
  Qiudi Jiang (2)
  Zheng Jiao (1)
  
  1. Department of Pharmacy, Huashan Hospital, Fudan University, 12 Wu Lu Mu Qi M Road, Shanghai, China, 200040
  2. Roche Innovation Center Shanghai, Shanghai, China
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1041

文摘

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.