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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Veröffentlicht in:Scientific reports 2019-07, Vol.9 (1), p.9619-14, Article 9619
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-45656-4