title: Predicting nonlinear pharmacokinetics of omeprazole enantiomers and racemic drug using physiologically based pharmacokinetic modeling and simulation: application to predict drug/genetic interactions.
abstract: OBJECTIVE
  The objective of this study is to develop a physiologically-based pharmacokinetic (PBPK) model for each omeprazole enantiomer that accounts for nonlinear PK of the two enantiomers as well as omeprazole racemic drug.
  
  
  METHODS
  By integrating in vitro, in silico and human PK data, we first developed PBPK models for each enantiomer. Simulation of racemic omeprazole PK was accomplished by combining enantiomer models that allow mutual drug interactions to occur.
  
  
  RESULTS
  The established PBPK models for the first time satisfactorily predicted the nonlinear PK of esomeprazole, R-omeprazole and the racemic drug. The modeling exercises revealed that the strong time-dependent inhibition of CYP2C19 by esomeprazole greatly altered the R-omeprazole PK following administration of racemic omeprazole as in contrast to R-omeprazole given alone. When PBPK models incorporated both autoinhibition of each enantiomer and mutual interactions, the ratios between predicted and observed AUC following single and multiple dosing of omeprazole were 0.97 and 0.94, respectively.
  
  
  CONCLUSIONS
  PBPK models of omeprazole enantiomers and racemic drug were developed. These models can be utilized to assess CYP2C19-mediated drug and genetic interaction potential for omeprazole and esomeprazole.
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.forename: Lu
authors.initials: L
authors.lastname: Gaohua
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.forename: Masoud
authors.initials: M
authors.lastname: Jamei
authors.forename: Shiew-Mei
authors.initials: SM
authors.lastname: Huang
authors.forename: Edward D
authors.initials: ED
authors.lastname: Bashaw
authors.forename: Sue-Chih
authors.initials: SC
authors.lastname: Lee
mesh_terms: D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism; D015195:Drug Design; D005544:Forecasting; D006801:Humans; D017711:Nonlinear Dynamics; D009853:Omeprazole / Q000737:chemistry / Q000493:pharmacokinetics*; D010597:Pharmacogenetics / Q000379:methods*; D013237:Stereoisomerism
chemical_list: C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole