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

ABSTRACT: 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.

SUBMITTER: McAleer CW

PROVIDER: S-EPMC6610665 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

McAleer Christopher W CW Pointon Amy A Long Christopher J CJ Brighton Rocky L RL Wilkin Benjamin D BD Bridges L Richard LR Narasimhan Sriram Narasimham N Fabre Kristin K McDougall Robin R Muse Victorine P VP Mettetal Jerome T JT Srivastava Abhishek A Williams Dominic D Schnepper Mark T MT Roles Jeff L JL Shuler Michael L ML Hickman James J JJ Ewart Lorna L

Scientific reports 20190703 1

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 c ...[more]

PMID: 31270362

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Dataset Information

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

Publications

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

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