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

Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft

Thomas J. Raub, Graham N. Wishart, Palaniappan Kulanthaivel, Brian A. Staton, Rose T. Ajamie, Geri A. Sawada, Lawrence M. Gelbert, Harlan E. Shannon, Concepcion Sanchez-Martinez and Alfonso De Dios
Drug Metabolism and Disposition September 2015, 43 (9) 1360-1371; DOI: https://doi.org/10.1124/dmd.114.062745
Thomas J. Raub
Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Graham N. Wishart
Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Palaniappan Kulanthaivel
Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brian A. Staton
Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rose T. Ajamie
Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Geri A. Sawada
Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lawrence M. Gelbert
Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Harlan E. Shannon
Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Concepcion Sanchez-Martinez
Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alfonso De Dios
Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)
  • 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 + SI
  • PDF
Loading

Abstract

Effective treatments for primary brain tumors and brain metastases represent a major unmet medical need. Targeting the CDK4/CDK6-cyclin D1-Rb-p16/ink4a pathway using a potent CDK4 and CDK6 kinase inhibitor has potential for treating primary central nervous system tumors such as glioblastoma and some peripheral tumors with high incidence of brain metastases. We compared central nervous system exposures of two orally bioavailable CDK4 and CDK6 inhibitors: abemaciclib, which is currently in advanced clinical development, and palbociclib (IBRANCE; Pfizer), which was recently approved by the U.S. Food and Drug Administration. Abemaciclib antitumor activity was assessed in subcutaneous and orthotopic glioma models alone and in combination with standard of care temozolomide (TMZ). Both inhibitors were substrates for xenobiotic efflux transporters P-glycoprotein and breast cancer resistant protein expressed at the blood–brain barrier. Brain Kp,uu values were less than 0.2 after an equimolar intravenous dose indicative of active efflux but were approximately 10-fold greater for abemaciclib than palbociclib. Kp,uu increased 2.8- and 21-fold, respectively, when similarly dosed in P-gp–deficient mice. Abemaciclib had brain area under the curve (0–24 hours) Kp,uu values of 0.03 in mice and 0.11 in rats after a 30 mg/kg p.o. dose. Orally dosed abemaciclib significantly increased survival in a rat orthotopic U87MG xenograft model compared with vehicle-treated animals, and efficacy coincided with a dose-dependent increase in unbound plasma and brain exposures in excess of the CDK4 and CDK6 Ki values. Abemaciclib increased survival time of intracranial U87MG tumor-bearing rats similar to TMZ, and the combination of abemaciclib and TMZ was additive or greater than additive. These data show that abemaciclib crosses the blood–brain barrier and confirm that both CDK4 and CDK6 inhibitors reach unbound brain levels in rodents that are expected to produce enzyme inhibition; however, abemaciclib brain levels are reached more efficiently at presumably lower doses than palbociclib and are potentially on target for a longer period of time.

Footnotes

    • Received December 16, 2014.
    • Accepted July 2, 2015.
  • ↵1 Current affiliation: Advion Bioanalytical Laboratories, A Quintiles Company, Indianapolis, Indiana.

  • ↵2 Current affiliation: Division of Hematology/Oncology, Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.

  • All Lilly authors are or were Eli Lilly and Company employees and shareholders. This research was supported by Eli Lilly and Company.

  • dx.doi.org/10.1124/dmd.114.062745.

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

  • Copyright © 2015 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: 43 (9)
Drug Metabolism and Disposition
Vol. 43, Issue 9
1 Sep 2015
  • 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.
Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft
(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

CDK4 and CDK6 Inhibitor Abemaciclib Crosses the Blood–Brain Barrier

Thomas J. Raub, Graham N. Wishart, Palaniappan Kulanthaivel, Brian A. Staton, Rose T. Ajamie, Geri A. Sawada, Lawrence M. Gelbert, Harlan E. Shannon, Concepcion Sanchez-Martinez and Alfonso De Dios
Drug Metabolism and Disposition September 1, 2015, 43 (9) 1360-1371; DOI: https://doi.org/10.1124/dmd.114.062745

Citation Manager Formats

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

Share
Research ArticleArticle

CDK4 and CDK6 Inhibitor Abemaciclib Crosses the Blood–Brain Barrier

Thomas J. Raub, Graham N. Wishart, Palaniappan Kulanthaivel, Brian A. Staton, Rose T. Ajamie, Geri A. Sawada, Lawrence M. Gelbert, Harlan E. Shannon, Concepcion Sanchez-Martinez and Alfonso De Dios
Drug Metabolism and Disposition September 1, 2015, 43 (9) 1360-1371; DOI: https://doi.org/10.1124/dmd.114.062745
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Metabolic enzymes in nintedanib metabolism
  • Mechanism of AO Inactivation by Hydralazine
  • Warfarin PBPK modeling with target binding
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