Predicting Nonlinear Pharmacokinetics of Omeprazole Enantiomers and Racemic Drug Using Physiologically Based Pharmacokinetic Modeling and Simulation: Application to Predict Drug/Genetic Interactions

ABSTRACT Purpose 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 f...

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Bibliographic Details
Published in:Pharmaceutical research 2014-08, Vol.31 (8), p.1919-1929
Main Authors: Wu, Fang, Gaohua, Lu, Zhao, Ping, Jamei, Masoud, Huang, Shiew-Mei, Bashaw, Edward D., Lee, Sue-Chih
Format: Article
Language:English
Subjects:
Biochemistry
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Cytochrome P-450 CYP2C19 - metabolism
Drug Design
Forecasting
Gastroesophageal reflux
Humans
Medical Law
Nonlinear Dynamics
Omeprazole - chemistry
Omeprazole - pharmacokinetics
Pharmacogenetics - methods
Pharmacology
Pharmacology/Toxicology
Pharmacy
Research Paper
Stereoisomerism
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Summary:ABSTRACT Purpose 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.
ISSN:0724-8741
1573-904X
DOI:10.1007/s11095-013-1293-z