On the Potential of in Vitro Organ-Chip Models to Define Temporal Pharmacokinetic-Pharmacodynamic Relationships

Christopher W McAleer, Amy Pointon, Christopher J Long, Rocky L Brighton, Benjamin D Wilkin, L Richard Bridges, Narasimham Narasimhan Sriram, Kristin Fabre, Robin McDougall, Victorine P Muse, Jerome T Mettetal, etc.

Sci Rep. 2019 Jul 3;9(1):9619.

PMID: 31270362

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.