title: Population pharmacokinetics of mycophenolic acid and its main glucuronide metabolite: a comparison between healthy Chinese and Caucasian subjects receiving mycophenolate mofetil.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacy, Huashan Hospital, Fudan University, 12 Wu Lu Mu Qi M Road, Shanghai, China, 200040.
authors.forename: Jing
authors.initials: J
authors.lastname: Ling
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.forename: Qiudi
authors.initials: Q
authors.lastname: Jiang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Jiao
mesh_terms: D000328:Adult; D044466:Asian People; D005260:Female; D020719:Glucuronides / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D044465:White People; D055815:Young Adult
chemical_list: D020719:Glucuronides; D007166:Immunosuppressive Agents; C113145:mycophenolic acid glucuronide; D009173:Mycophenolic Acid