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

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

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 types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Discovery / methods
  • Humans
  • Lab-On-A-Chip Devices
  • Microchip Analytical Procedures* / methods
  • Models, Biological
  • Models, Theoretical*
  • Organ Specificity
  • Pharmacokinetics*
  • Translational Medical Research / methods