Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • 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
  • 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
    • 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
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Disposition and Metabolism of [14C]Lemborexant in Healthy Human Subjects and Characterization of Its Circulating Metabolites

Takashi Ueno, Tomomi Ishida, Jagadeesh Aluri, Michiyuki Suzuki, Carsten T. Beuckmann, Takaaki Kameyama, Shoji Asakura and Kazutomi Kusano
Drug Metabolism and Disposition January 2021, 49 (1) 31-38; DOI: https://doi.org/10.1124/dmd.120.000229
Takashi Ueno
Eisai Co., Ltd., Ibaraki, Japan (T.U., T.I., C.T.B., T.K., S.A., K.K.); Eisai Inc., Woodcliff Lake, New Jersey (J.A.); and EA Pharma Co., Ltd., Tokyo, Japan (M.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Takashi Ueno
Tomomi Ishida
Eisai Co., Ltd., Ibaraki, Japan (T.U., T.I., C.T.B., T.K., S.A., K.K.); Eisai Inc., Woodcliff Lake, New Jersey (J.A.); and EA Pharma Co., Ltd., Tokyo, Japan (M.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jagadeesh Aluri
Eisai Co., Ltd., Ibaraki, Japan (T.U., T.I., C.T.B., T.K., S.A., K.K.); Eisai Inc., Woodcliff Lake, New Jersey (J.A.); and EA Pharma Co., Ltd., Tokyo, Japan (M.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michiyuki Suzuki
Eisai Co., Ltd., Ibaraki, Japan (T.U., T.I., C.T.B., T.K., S.A., K.K.); Eisai Inc., Woodcliff Lake, New Jersey (J.A.); and EA Pharma Co., Ltd., Tokyo, Japan (M.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carsten T. Beuckmann
Eisai Co., Ltd., Ibaraki, Japan (T.U., T.I., C.T.B., T.K., S.A., K.K.); Eisai Inc., Woodcliff Lake, New Jersey (J.A.); and EA Pharma Co., Ltd., Tokyo, Japan (M.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Takaaki Kameyama
Eisai Co., Ltd., Ibaraki, Japan (T.U., T.I., C.T.B., T.K., S.A., K.K.); Eisai Inc., Woodcliff Lake, New Jersey (J.A.); and EA Pharma Co., Ltd., Tokyo, Japan (M.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shoji Asakura
Eisai Co., Ltd., Ibaraki, Japan (T.U., T.I., C.T.B., T.K., S.A., K.K.); Eisai Inc., Woodcliff Lake, New Jersey (J.A.); and EA Pharma Co., Ltd., Tokyo, Japan (M.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kazutomi Kusano
Eisai Co., Ltd., Ibaraki, Japan (T.U., T.I., C.T.B., T.K., S.A., K.K.); Eisai Inc., Woodcliff Lake, New Jersey (J.A.); and EA Pharma Co., Ltd., Tokyo, Japan (M.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

Lemborexant is a novel dual orexin receptor antagonist recently approved for the treatment of insomnia in the United States and Japan. Here, disposition and metabolic profiles were investigated in healthy human subjects. After single oral administration of 10 mg [14C]lemborexant (100 µCi), plasma concentrations of lemborexant and radioactivity peaked at 1 hour postdose and decreased biphasically. Cumulative recovery of the administered radioactivity within 480 hours was 86.5% of the dose, with 29.1% in urine and 57.4% in feces. Unchanged lemborexant was not detected in urine but accounted for 13.0% of the dose in feces, suggesting that the main elimination pathway of lemborexant was metabolism. Metabolite analyses revealed that the major metabolic pathways of lemborexant are oxidation of the dimethylpyrimidine moiety and subsequent further oxidation and/or glucuronidation. In plasma, lemborexant was the dominant component, accounting for 26.5% of total drug-related exposure. M4, M9, M10, and M18 were detected as the major radioactive components; M10 was the only metabolite exceeding 10% of total drug-related exposure. Although M4, M9, and M10 showed binding affinity for orexin receptors comparable to that of lemborexant, their contributions to the sleep-promoting effects of lemborexant are likely low because of the limited brain penetration by P-glycoprotein. Exposure comparison between humans and nonclinical toxicology species confirmed that plasma exposure of M10 was higher in at least one animal species compared with that in humans, indicating that there is no disproportionate metabolite in humans, as defined by International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use M3(R2) and U.S. Food and Drug Administration Metabolite in Safety Testing guidance; therefore, no additional toxicology studies are needed.

SIGNIFICANCE STATEMENT This study provides detailed data of the disposition and metabolism of lemborexant, a novel therapeutic drug for insomnia, in humans, as well as a characterization of the circulating metabolites and assessment of their contributions to efficacy and safety. The information presented herein furthers our understanding of the pharmacokinetic profiles of lemborexant and its metabolites and will promote the safe and effective use of lemborexant in the clinic.

Footnotes

    • Received August 28, 2020.
    • Accepted October 26, 2020.
  • All research was funded by Eisai Co., Ltd.

  • https://doi.org/10.1124/dmd.120.000229.

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

  • Copyright © 2020 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: 49 (1)
Drug Metabolism and Disposition
Vol. 49, Issue 1
1 Jan 2021
  • 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.
Disposition and Metabolism of [14C]Lemborexant in Healthy Human Subjects and Characterization of Its Circulating Metabolites
(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

ADME Properties of Lemborexant in Humans

Takashi Ueno, Tomomi Ishida, Jagadeesh Aluri, Michiyuki Suzuki, Carsten T. Beuckmann, Takaaki Kameyama, Shoji Asakura and Kazutomi Kusano
Drug Metabolism and Disposition January 1, 2021, 49 (1) 31-38; DOI: https://doi.org/10.1124/dmd.120.000229

Citation Manager Formats

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

ADME Properties of Lemborexant in Humans

Takashi Ueno, Tomomi Ishida, Jagadeesh Aluri, Michiyuki Suzuki, Carsten T. Beuckmann, Takaaki Kameyama, Shoji Asakura and Kazutomi Kusano
Drug Metabolism and Disposition January 1, 2021, 49 (1) 31-38; DOI: https://doi.org/10.1124/dmd.120.000229
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google 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

  • BSEP Function in Suspension Hepatocytes
  • Candesartan glucuronide serves as a CYP2C8 inhibitor
  • Role of AADAC on eslicarbazepine acetate hydrolysis
Show more Articles

Similar Articles

  • 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 © 2021 by the American Society for Pharmacology and Experimental Therapeutics