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Research ArticleArticle

Prediction of Crizotinib-Midazolam Interaction Using the Simcyp Population-Based Simulator: Comparison of CYP3A Time-Dependent Inhibition between Human Liver Microsomes versus Hepatocytes

Jialin Mao, Theodore R. Johnson, Zhongzhou Shen and Shinji Yamazaki
Drug Metabolism and Disposition February 2013, 41 (2) 343-352; DOI: https://doi.org/10.1124/dmd.112.049114
Jialin Mao
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development, San Diego, California
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Theodore R. Johnson
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development, San Diego, California
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Zhongzhou Shen
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development, San Diego, California
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Shinji Yamazaki
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development, San Diego, California
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Abstract

Crizotinib (Xalkori) is an orally available potent inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase and mesenchymal-epithelial transition factor. Objectives of the present study were as follows: 1) to characterize crizotinib time-dependent inhibition (TDI) potency for CYP3A in human liver microsomes (HLM) and cryopreserved human hepatocytes suspended in human plasma (HSP); 2) to characterize crizotinib enzyme induction potency on CYP3A4 in cryopreserved human hepatocytes; 3) to predict crizotinib steady-state plasma concentrations in patients (e.g., autoinhibition and autoinduction) using the mechanistic dynamic model, Simcyp population-based simulator; and 4) to predict a clinical crizotinib-midazolam interaction using the dynamic model as well as the static mathematical model. Crizotinib inactivation constant (KI) and maximum inactivation rate constant (kinact) for TDI were estimated as, respectively, 0.37 µM and 6.9 h−1 in HLM and 0.89 µM and 0.78 h−1 in HSP. Thus, crizotinib inactivation efficiency (kinact/KI) was ∼20-fold lower in HSP relative to HLM. Crizotinib Emax and EC50 for CYP3A4 induction (measured as mRNA expression) were estimated as 6.4- to 29-fold and 0.47 to 3.1 µM, respectively. Based on these in vitro parameters, the predicted crizotinib steady-state area under plasma concentration-time curve (AUC) with HLM-TDI was 2.1-fold higher than the observed AUC, whereas that with HSP-TDI was consistent with the observed result (≤1.1-fold). The increase in midazolam AUC with coadministration of crizotinib (21-fold) was significantly overpredicted using HLM-TDI, whereas the prediction using HSP-TDI (3.6-fold) was consistent with the observed result (3.7-fold). Collectively, the present study demonstrated the value of HSP to predict in vivo CYP3A-mediated drug-drug interaction.

Footnotes

  • ↵Embedded ImageThis article has supplemental material available at dmd@aspetjournals.org.

  • dx.doi.org/10.1124/dmd.112.049114

  • Received September 18, 2012.
  • Accepted November 5, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (2)
Drug Metabolism and Disposition
Vol. 41, Issue 2
1 Feb 2013
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Research ArticleArticle

Prediction of Crizotinib-Midazolam Interaction

Jialin Mao, Theodore R. Johnson, Zhongzhou Shen and Shinji Yamazaki
Drug Metabolism and Disposition February 1, 2013, 41 (2) 343-352; DOI: https://doi.org/10.1124/dmd.112.049114

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Research ArticleArticle

Prediction of Crizotinib-Midazolam Interaction

Jialin Mao, Theodore R. Johnson, Zhongzhou Shen and Shinji Yamazaki
Drug Metabolism and Disposition February 1, 2013, 41 (2) 343-352; DOI: https://doi.org/10.1124/dmd.112.049114
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