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
OtherArticle

Revisiting nonlinear bosentan pharmacokinetics by PBPK modeling: Target binding, albeit not a major contributor to nonlinearity, can offer prediction of target occupancy

Satoshi Koyama, Kota Toshimoto, Wooin Lee, Yasunori Aoki and Yuichi Sugiyama
Drug Metabolism and Disposition February 8, 2021, DMD-AR-2020-000023; DOI: https://doi.org/10.1124/dmd.120.000023
Satoshi Koyama
1Delta Mex Inc., Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Satoshi Koyama
Kota Toshimoto
2Sugiyama Laboratory, RIKEN Cluster for Science, Technology and Innovation Hub, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wooin Lee
3Seoul National University, Korea, Republic of
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Wooin Lee
Yasunori Aoki
4National Institute of Informatics, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuichi Sugiyama
5Sugiyama Laboratory, RIKEN Innovation Center, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: ychi.sugiyama@riken.jp
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

Bosentan is a high-affinity antagonist of endothelin receptors and one of the earliest examples for target-mediated drug disposition (a type of nonlinear pharmacokinetics (PKs) caused by saturable target binding). The previous physiologically-based PK (PBPK) modeling indicated that the nonlinear PKs of bosentan was explainable by considering saturable hepatic uptake. However, it remained unexamined to what extent the saturable target binding contributes to the nonlinear PKs of bosentan. Here, we developed a PBPK model incorporating saturable target binding and hepatic uptake, and analyzed the clinical bosentan PK data using the Cluster Gauss-Newton method (CGNM). The PBPK model without target binding fell short in capturing the bosentan concentrations below 100 nM, based on the PK profiles and the Goodness-of-Fit plot. Both global and local identifiability analyses (using the CGNM and Fisher Information Matrix, respectively) informed that the target binding parameters were identifiable only if the observations from the lowest dose (10 mg) were included. By analyzing blood PK profiles alone, the PBPK model with target binding yielded practically identifiable target binding parameters and predicted the maximum target occupancies of 0.6-0.8 at clinical bosentan doses. Our results indicate that target binding, albeit not a major contributor to the nonlinear bosentan PKs, may offer a prediction of target occupancy from blood PK profiles alone and potential guidance on achieving optimal efficacy outcomes, under the condition when the high-affinity drug target is responsible for the efficacy of interest, and when the dose ranges cover varying degrees of target binding.

Significance Statement By incorporating saturable target binding, our PBPK model predicted in vivo target occupancy of bosentan based only on the blood concentration–time profiles obtained from a wide range of doses. Our analysis highlights the potential utility of PBPK models that incorporate target binding in predicting target occupancy in vivo.

  • endothelin receptors
  • physiologically-based pharmacokinetic modeling/PBPK
  • © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution CC BY License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 49 (3)
Drug Metabolism and Disposition
Vol. 49, Issue 3
1 Mar 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.
Revisiting nonlinear bosentan pharmacokinetics by PBPK modeling: Target binding, albeit not a major contributor to nonlinearity, can offer prediction of target occupancy
(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
OtherArticle

Target occupancy of bosentan estimated by PBPK modeling

Satoshi Koyama, Kota Toshimoto, Wooin Lee, Yasunori Aoki and Yuichi Sugiyama
Drug Metabolism and Disposition February 8, 2021, DMD-AR-2020-000023; DOI: https://doi.org/10.1124/dmd.120.000023

Citation Manager Formats

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

Target occupancy of bosentan estimated by PBPK modeling

Satoshi Koyama, Kota Toshimoto, Wooin Lee, Yasunori Aoki and Yuichi Sugiyama
Drug Metabolism and Disposition February 8, 2021, DMD-AR-2020-000023; DOI: https://doi.org/10.1124/dmd.120.000023
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
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • In Vivo Functional Effects of CYP2C9 M1L
  • Clearance pathways: fevipiprant with probenecid perpetrator
  • Predicting Volume of Distribution from In Vitro Parameters
Show more Article

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