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

Significant Species Difference in Amide Hydrolysis of GDC-0834, a Novel Potent and Selective Bruton's Tyrosine Kinase Inhibitor

Lichuan Liu, Jason S. Halladay, Young Shin, Susan Wong, Melis Coraggio, Hank La, Matthew Baumgardner, Hoa Le, Sashi Gopaul, Jason Boggs, Peter Kuebler, John C. Davis Jr., X. Charlene Liao, Joseph W. Lubach, Alan Deese, C. Gregory Sowell, Kevin S. Currie, Wendy B. Young, S. Cyrus Khojasteh, Cornelis E. C. A. Hop and Harvey Wong
Drug Metabolism and Disposition October 2011, 39 (10) 1840-1849; DOI: https://doi.org/10.1124/dmd.111.040840
Lichuan Liu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jason S. Halladay
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Young Shin
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Susan Wong
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Melis Coraggio
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hank La
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew Baumgardner
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hoa Le
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sashi Gopaul
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jason Boggs
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter Kuebler
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John C. Davis Jr.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
X. Charlene Liao
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joseph W. Lubach
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alan Deese
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
C. Gregory Sowell
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kevin S. Currie
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wendy B. Young
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S. Cyrus Khojasteh
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cornelis E. C. A. Hop
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Harvey Wong
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

(R)-N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (GDC-0834) is a potent and selective inhibitor of Bruton's tyrosine kinase (BTK), investigated as a potential treatment for rheumatoid arthritis. In vitro metabolite identification studies in hepatocytes revealed predominant formation of an inactive metabolite (M1) via amide hydrolysis in human. The formation of M1 appeared to be NADPH-independent in human liver microsomes. M1 was found in only minor to moderate quantities in plasma from preclinical species dosed with GDC-0834. Human clearance predictions using various methodologies resulted in estimates ranging from low to high. In addition, GDC-0834 exhibited low clearance in PXB chimeric mice with humanized liver. Uncertainty in human pharmacokinetic prediction and high interest in a BTK inhibitor for clinical evaluation prompted an investigational new drug strategy, in which GDC-0834 was rapidly advanced to a single-dose human clinical trial. GDC-0834 plasma concentrations in humans were below the limit of quantitation (<1 ng/ml) in most samples from the cohorts dosed orally at 35 and 105 mg. In contrast, substantial plasma concentrations of M1 were observed. In human plasma and urine, only M1 and its sequential metabolites were identified. The formation kinetics of M1 was evaluated in rat, dog, monkey, and human liver microsomes in the absence of NADPH. The maximum rate of M1 formation (Vmax) was substantially higher in human compared with that in other species. In contrast, the Michaelis-Menten constant (Km) was comparable among species. Intrinsic clearance (Vmax/Km) of GDC-0834 from M1 formation in human was 23- to 169-fold higher than observed in rat, dog, and monkey.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.111.040840.

  • ABBREVIATIONS:

    BTK
    Bruton's tyrosine kinase
    RA
    rheumatoid arthritis
    GDC-0834
    (R)-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide
    PK
    pharmacokinetic(s)
    SCID
    severe combined immunodeficiency disease
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    DMEM
    Dulbecco's modified Eagle's medium
    MLP
    maximum lifespan potential
    IVIVE
    in vitro/in vivo extrapolation
    LM
    liver microsome(s)
    AUC
    area under the concentration-time curve
    P450
    cytochrome P450
    IND
    investigational new drug.

  • Received May 23, 2011.
  • Accepted July 6, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

 

DMD articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 39 (10)
Drug Metabolism and Disposition
Vol. 39, Issue 10
1 Oct 2011
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • 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.
Significant Species Difference in Amide Hydrolysis of GDC-0834, a Novel Potent and Selective Bruton's Tyrosine Kinase Inhibitor
(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

AMIDE HYDROLYSIS IN HUMAN

Lichuan Liu, Jason S. Halladay, Young Shin, Susan Wong, Melis Coraggio, Hank La, Matthew Baumgardner, Hoa Le, Sashi Gopaul, Jason Boggs, Peter Kuebler, John C. Davis, X. Charlene Liao, Joseph W. Lubach, Alan Deese, C. Gregory Sowell, Kevin S. Currie, Wendy B. Young, S. Cyrus Khojasteh, Cornelis E. C. A. Hop and Harvey Wong
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1840-1849; DOI: https://doi.org/10.1124/dmd.111.040840

Citation Manager Formats

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

Share
Research ArticleArticle

AMIDE HYDROLYSIS IN HUMAN

Lichuan Liu, Jason S. Halladay, Young Shin, Susan Wong, Melis Coraggio, Hank La, Matthew Baumgardner, Hoa Le, Sashi Gopaul, Jason Boggs, Peter Kuebler, John C. Davis, X. Charlene Liao, Joseph W. Lubach, Alan Deese, C. Gregory Sowell, Kevin S. Currie, Wendy B. Young, S. Cyrus Khojasteh, Cornelis E. C. A. Hop and Harvey Wong
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1840-1849; DOI: https://doi.org/10.1124/dmd.111.040840
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Results
    • Discussion
    • Authorship Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Warfarin PBPK Model with TMDD Mechanism
  • Identification of payload-containing catabolites of ADCs
  • PK Interactions of Licorice with Cytochrome P450s
Show more Articles

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