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 |
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Format: | Artikel |
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. |
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ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-019-45656-4 |