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- Title
On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships.
- Authors
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
- 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.
- Publication
Scientific Reports, 2019, Vol 9, Issue 1, pN.PAG
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-019-45656-4