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Physiologically based pharmacokinetic modelling to predict the clinical effect of CYP3A inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment
PURPOSE: Esaxerenone is a novel, oral, nonsteroidal treatment for hypertension. Physiologically based pharmacokinetic (PBPK) modelling was performed to predict the drug–drug interaction (DDI) effect of cytochrome P450 (CYP)3A modulators on esaxerenone pharmacokinetics in healthy subjects and subject...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724184/ https://www.ncbi.nlm.nih.gov/pubmed/34415382 http://dx.doi.org/10.1007/s00228-021-03194-x |
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author | Watanabe, Akiko Ishizuka, Tomoko Yamada, Makiko Igawa, Yoshiyuki Shimizu, Takako Ishizuka, Hitoshi |
author_facet | Watanabe, Akiko Ishizuka, Tomoko Yamada, Makiko Igawa, Yoshiyuki Shimizu, Takako Ishizuka, Hitoshi |
author_sort | Watanabe, Akiko |
collection | PubMed |
description | PURPOSE: Esaxerenone is a novel, oral, nonsteroidal treatment for hypertension. Physiologically based pharmacokinetic (PBPK) modelling was performed to predict the drug–drug interaction (DDI) effect of cytochrome P450 (CYP)3A modulators on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment. METHODS: In our PBPK model, the fraction of esaxerenone metabolised by CYP3A was estimated from mass-balance data and verified and optimised by clinical DDI study results with strong CYP3A modulators. The model was also verified by the observed pharmacokinetics after multiple oral dosing and by the effect of hepatic impairment on esaxerenone pharmacokinetics. The model was applied to predict the DDI effects on esaxerenone pharmacokinetics with untested CYP3A modulators in healthy subjects and with strong CYP3A modulators in subjects with hepatic impairment. RESULTS: The PBPK model well described esaxerenone pharmacokinetics after multiple oral dosing. The predicted fold changes in esaxerenone plasma exposure after coadministration with strong CYP3A modulators were comparable with the observed data (1.53-fold with itraconazole and 0.31-fold with rifampicin). Predicted DDIs with untested moderate CYP3A modulators were less than the observed DDI with strong CYP3A modulators. The PBPK model also described the effect of hepatic impairment on esaxerenone plasma exposure. The predicted DDI results with strong CYP3A modulators in subjects with hepatic impairment indicate that, for concomitant use of CYP3A modulators, caution is advised for subjects with hepatic impairment, as is for healthy subjects. CONCLUSION: The PBPK model developed predicted esaxerenone pharmacokinetics and DDIs and informed concurrent use of esaxerenone with CYP3A modulators. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00228-021-03194-x. |
format | Online Article Text |
id | pubmed-8724184 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-87241842022-01-13 Physiologically based pharmacokinetic modelling to predict the clinical effect of CYP3A inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment Watanabe, Akiko Ishizuka, Tomoko Yamada, Makiko Igawa, Yoshiyuki Shimizu, Takako Ishizuka, Hitoshi Eur J Clin Pharmacol Pharmacokinetics and Disposition PURPOSE: Esaxerenone is a novel, oral, nonsteroidal treatment for hypertension. Physiologically based pharmacokinetic (PBPK) modelling was performed to predict the drug–drug interaction (DDI) effect of cytochrome P450 (CYP)3A modulators on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment. METHODS: In our PBPK model, the fraction of esaxerenone metabolised by CYP3A was estimated from mass-balance data and verified and optimised by clinical DDI study results with strong CYP3A modulators. The model was also verified by the observed pharmacokinetics after multiple oral dosing and by the effect of hepatic impairment on esaxerenone pharmacokinetics. The model was applied to predict the DDI effects on esaxerenone pharmacokinetics with untested CYP3A modulators in healthy subjects and with strong CYP3A modulators in subjects with hepatic impairment. RESULTS: The PBPK model well described esaxerenone pharmacokinetics after multiple oral dosing. The predicted fold changes in esaxerenone plasma exposure after coadministration with strong CYP3A modulators were comparable with the observed data (1.53-fold with itraconazole and 0.31-fold with rifampicin). Predicted DDIs with untested moderate CYP3A modulators were less than the observed DDI with strong CYP3A modulators. The PBPK model also described the effect of hepatic impairment on esaxerenone plasma exposure. The predicted DDI results with strong CYP3A modulators in subjects with hepatic impairment indicate that, for concomitant use of CYP3A modulators, caution is advised for subjects with hepatic impairment, as is for healthy subjects. CONCLUSION: The PBPK model developed predicted esaxerenone pharmacokinetics and DDIs and informed concurrent use of esaxerenone with CYP3A modulators. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00228-021-03194-x. Springer Berlin Heidelberg 2021-08-20 2022 /pmc/articles/PMC8724184/ /pubmed/34415382 http://dx.doi.org/10.1007/s00228-021-03194-x Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Pharmacokinetics and Disposition Watanabe, Akiko Ishizuka, Tomoko Yamada, Makiko Igawa, Yoshiyuki Shimizu, Takako Ishizuka, Hitoshi Physiologically based pharmacokinetic modelling to predict the clinical effect of CYP3A inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment |
title | Physiologically based pharmacokinetic modelling to predict the clinical effect of CYP3A inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment |
title_full | Physiologically based pharmacokinetic modelling to predict the clinical effect of CYP3A inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment |
title_fullStr | Physiologically based pharmacokinetic modelling to predict the clinical effect of CYP3A inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment |
title_full_unstemmed | Physiologically based pharmacokinetic modelling to predict the clinical effect of CYP3A inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment |
title_short | Physiologically based pharmacokinetic modelling to predict the clinical effect of CYP3A inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment |
title_sort | physiologically based pharmacokinetic modelling to predict the clinical effect of cyp3a inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment |
topic | Pharmacokinetics and Disposition |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724184/ https://www.ncbi.nlm.nih.gov/pubmed/34415382 http://dx.doi.org/10.1007/s00228-021-03194-x |
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