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Pharmaceutical Research

, Volume 31, Issue 8, pp 1919–1929 | Cite as

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

  • Fang Wu
  • Lu Gaohua
  • Ping Zhao
  • Masoud Jamei
  • Shiew-Mei Huang
  • Edward D. Bashaw
  • Sue-Chih Lee
Research Paper

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.

KEY WORDS

esomeprazole nonlinear pharmacokinetics omeprazole physiologically based pharmacokinetic (PBPK) model racemic drug 

ABBREVIATIONS

ADME

Absorption, distribution, metabolism and excretion

ASA

Automated sensitivity analysis

CLint

Intrinsic clearance

DDI

Drug-drug interaction

EM

Extensive metabolizers

HLM

Human liver microsomes

PBPK

Physiologically based pharmacokinetic modeling

PK

Pharmacokinetics

PM

Poor metabolizers

TDI

Time-dependent inhibition

Vss

Volume of distribution at steady state

WT

Wild type

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank Professor Amin Rostami-Hodjegan from the University of Manchester for his valuable scientific input. This project was supported by FDA’s Critical Path Fellowship. This project was also supported in part by an appointment to the ORISE Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an agreement between the U.S. Department of Energy and CDER. The views presented in this manuscript are those of authors and do not necessarily reflect the official view of the FDA.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC (outside the USA) 2014

Authors and Affiliations

  • Fang Wu
    • 1
  • Lu Gaohua
    • 2
  • Ping Zhao
    • 1
  • Masoud Jamei
    • 2
  • Shiew-Mei Huang
    • 1
  • Edward D. Bashaw
    • 1
  • Sue-Chih Lee
    • 1
  1. 1.Office of Clinical Pharmacology, Office of Translational Sciences Center for Drug Evaluation and ResearchFood and Drug AdministrationSilver SpringUSA
  2. 2.SIMCYP Limited, Blades Enterprise CentreSheffieldUK

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