Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Drug Metabolism & Disposition
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
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 November 5, 2012, dmd.112.049114; DOI: https://doi.org/10.1124/dmd.112.049114
Jialin Mao
Pfizer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Theodore R Johnson
Pfizer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zhongzhou Shen
Pfizer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shinji Yamazaki
Pfizer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: shinji.yamazaki@pfizer.com
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

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 to: 1) characterize crizotinib time-dependent inhibition (TDI) potency for CYP3A in human liver microsomes (HLM) and cryopreserved human hepatocytes suspended in plasma (HSP), 2) characterize crizotinib enzyme induction potency on CYP3A4 in cryopreserved human hepatocytes (HEP), 3) predict crizotinib steady-state plasma concentrations in patients (e.g., autoinhibition and autoinduction) using the mechanistic dynamic model, Simcyp population-based simulator, and 4) 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 approximately 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 co-administration of crizotinib (21-fold) was significantly over-predicted 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.

  • CYP induction
  • CYP inhibition
  • CYP3A
  • drug-drug interactions
  • hepatocytes
  • in vitro-in vivo prediction
  • microsomes
  • physiologically-based pharmacokinetics
  • Received September 19, 2012.
  • Accepted November 5, 2012.
  • The American Society for Pharmacology and Experimental Therapeutics
Next
Back to top

In this issue

Drug Metabolism and Disposition: 51 (10)
Drug Metabolism and Disposition
Vol. 51, Issue 10
1 Oct 2023
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Drug Metabolism & Disposition article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Prediction of Crizotinib-Midazolam Interaction Using the Simcyp Population-Based Simulator: Comparison of CYP3A Time-Dependent Inhibition Between Human Liver Microsomes Versus Hepatocytes
(Your Name) has forwarded a page to you from Drug Metabolism & Disposition
(Your Name) thought you would be interested in this article in Drug Metabolism & Disposition.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
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 November 5, 2012, dmd.112.049114; DOI: https://doi.org/10.1124/dmd.112.049114

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
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 November 5, 2012, dmd.112.049114; DOI: https://doi.org/10.1124/dmd.112.049114
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Ontogeny of CPPGL
  • Expression of AKR and SDR Isoforms in the Human Intestine
  • Is Protein-Mediated Uptake Effect a Real Phenomenon?
Show more Article

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About DMD
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-009X (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics