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Sci Rep. 2019 Jul 3;9(1):9619. doi: 10.1038/s41598-019-45656-4.

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

Author information

1
Hesperos, Inc., 3259 Progress Dr., Room 158, Orlando, FL, 32826-3230, USA.
2
Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
3
Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Waltham, USA.
4
NanoScience Technology Center, 12424 Research Parkway, Suite 400, Orlando, FL, 32826, USA.
5
Hesperos, Inc., 3259 Progress Dr., Room 158, Orlando, FL, 32826-3230, USA. jhickman@hesperosinc.com.
6
NanoScience Technology Center, 12424 Research Parkway, Suite 400, Orlando, FL, 32826, USA. jhickman@hesperosinc.com.
7
Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK. lorna.ewart@astrazeneca.com.

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.

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