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On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships

Functional human-on-a-chip systems hold great promise to enable quantitative translation to in vivo outcomes. Here, we explored this concept using a pumpless heart only and heart:liver system to evaluate the temporal pharmacokinetic/pharmacodynamic (PKPD) relationship for terfenadine. There was a ti...

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Autores principales: McAleer, Christopher W., Pointon, Amy, Long, Christopher J., Brighton, Rocky L., Wilkin, Benjamin D., Bridges, L. Richard, Narasimhan Sriram, Narasimham, Fabre, Kristin, McDougall, Robin, Muse, Victorine P., Mettetal, Jerome T., Srivastava, Abhishek, Williams, Dominic, Schnepper, Mark T., Roles, Jeff L., Shuler, Michael L., Hickman, James J., Ewart, Lorna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610665/
https://www.ncbi.nlm.nih.gov/pubmed/31270362
http://dx.doi.org/10.1038/s41598-019-45656-4
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author McAleer, Christopher W.
Pointon, Amy
Long, Christopher J.
Brighton, Rocky L.
Wilkin, Benjamin D.
Bridges, L. Richard
Narasimhan Sriram, Narasimham
Fabre, Kristin
McDougall, Robin
Muse, Victorine P.
Mettetal, Jerome T.
Srivastava, Abhishek
Williams, Dominic
Schnepper, Mark T.
Roles, Jeff L.
Shuler, Michael L.
Hickman, James J.
Ewart, Lorna
author_facet McAleer, Christopher W.
Pointon, Amy
Long, Christopher J.
Brighton, Rocky L.
Wilkin, Benjamin D.
Bridges, L. Richard
Narasimhan Sriram, Narasimham
Fabre, Kristin
McDougall, Robin
Muse, Victorine P.
Mettetal, Jerome T.
Srivastava, Abhishek
Williams, Dominic
Schnepper, Mark T.
Roles, Jeff L.
Shuler, Michael L.
Hickman, James J.
Ewart, Lorna
author_sort McAleer, Christopher W.
collection PubMed
description Functional human-on-a-chip systems hold great promise to enable quantitative translation to in vivo outcomes. Here, we explored this concept using a pumpless heart only and heart:liver system to evaluate the temporal pharmacokinetic/pharmacodynamic (PKPD) relationship for terfenadine. There was a time dependent drug-induced increase in field potential duration in the cardiac compartment in response to terfenadine and that response was modulated using a metabolically competent liver module that converted terfenadine to fexofenadine. Using this data, a mathematical model was developed to predict the effect of terfenadine in preclinical species. Developing confidence that microphysiological models could have a transformative effect on drug discovery, we also tested a previously discovered proprietary AstraZeneca small molecule and correctly determined the cardiotoxic response to its metabolite in the heart:liver system. Overall our findings serve as a guiding principle to future investigations of temporal concentration response relationships in these innovative in vitro models, especially, if validated across multiple time frames, with additional pharmacological mechanisms and molecules representing a broad chemical diversity.
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spelling pubmed-66106652019-07-15 On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships McAleer, Christopher W. Pointon, Amy Long, Christopher J. Brighton, Rocky L. Wilkin, Benjamin D. Bridges, L. Richard Narasimhan Sriram, Narasimham Fabre, Kristin McDougall, Robin Muse, Victorine P. Mettetal, Jerome T. Srivastava, Abhishek Williams, Dominic Schnepper, Mark T. Roles, Jeff L. Shuler, Michael L. Hickman, James J. Ewart, Lorna Sci Rep Article Functional human-on-a-chip systems hold great promise to enable quantitative translation to in vivo outcomes. Here, we explored this concept using a pumpless heart only and heart:liver system to evaluate the temporal pharmacokinetic/pharmacodynamic (PKPD) relationship for terfenadine. There was a time dependent drug-induced increase in field potential duration in the cardiac compartment in response to terfenadine and that response was modulated using a metabolically competent liver module that converted terfenadine to fexofenadine. Using this data, a mathematical model was developed to predict the effect of terfenadine in preclinical species. Developing confidence that microphysiological models could have a transformative effect on drug discovery, we also tested a previously discovered proprietary AstraZeneca small molecule and correctly determined the cardiotoxic response to its metabolite in the heart:liver system. Overall our findings serve as a guiding principle to future investigations of temporal concentration response relationships in these innovative in vitro models, especially, if validated across multiple time frames, with additional pharmacological mechanisms and molecules representing a broad chemical diversity. Nature Publishing Group UK 2019-07-03 /pmc/articles/PMC6610665/ /pubmed/31270362 http://dx.doi.org/10.1038/s41598-019-45656-4 Text en © The Author(s) 2019 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
McAleer, Christopher W.
Pointon, Amy
Long, Christopher J.
Brighton, Rocky L.
Wilkin, Benjamin D.
Bridges, L. Richard
Narasimhan Sriram, Narasimham
Fabre, Kristin
McDougall, Robin
Muse, Victorine P.
Mettetal, Jerome T.
Srivastava, Abhishek
Williams, Dominic
Schnepper, Mark T.
Roles, Jeff L.
Shuler, Michael L.
Hickman, James J.
Ewart, Lorna
On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships
title On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships
title_full On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships
title_fullStr On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships
title_full_unstemmed On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships
title_short On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships
title_sort on the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610665/
https://www.ncbi.nlm.nih.gov/pubmed/31270362
http://dx.doi.org/10.1038/s41598-019-45656-4
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