title: Evaluating a physiologically based pharmacokinetic model for predicting the pharmacokinetics of midazolam in Chinese after oral administration.
abstract: OBJECTIVE
  To evaluate the SimCYP simulator ethnicity-specific population model for predicting the pharmacokinetics of midazolam, a typical CYP3A4/5 substrate, in Chinese after oral administration.
  
  
  METHODS
  The physiologically based pharmacokinetic (PBPK) model for midazolam was developed using a SimCYP population-based simulator incorporating Chinese population demographic, physiological and enzyme data. A clinical trial was conducted in 40 Chinese subjects (the half was females) receiving a single oral dose of 15 mg midazolam. The subjects were separated into 4 groups based on age (20-50, 51-65, 66-75, and above 76 years), and the pharmacokinetics profiles of each age- and gender-group were determined, and the results were used to verify the PBPK model.
  
  
  RESULTS
  Following oral administration, the simulated profiles of midazolam plasma concentrations over time in virtual Chinese were in good agreement with the observed profiles, as were AUC and Cmax. Moreover, for subjects of varying ages (20-80 years), the ratios of predicted to observed clearances were between 0.86 and 1.12.
  
  
  CONCLUSIONS
  The SimCYP PBPK model accurately predicted the pharmacokinetics of midazolam in Chinese from youth to old age. This study may provide novel insight into the prediction of CYP3A4/5-mediated pharmacokinetics in the Chinese population relative to Caucasians and other ethnic groups, which can support the rational design of bridging clinical trials.
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Hong-yun
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Clinical Pharmacology Department, Roche pRED China, Shanghai 201203, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008875:Middle Aged; D008954:Models, Biological; D055815:Young Adult
chemical_list: D006993:Hypnotics and Sedatives; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam