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.
CITATION STYLE
McAleer, C. W., Pointon, A., Long, C. J., Brighton, R. L., Wilkin, B. D., Bridges, L. R., … Ewart, L. (2019). On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships. Scientific Reports, 9(1). https://doi.org/10.1038/s41598-019-45656-4
Mendeley helps you to discover research relevant for your work.