A human population-based organotypic in vitro model for cardiotoxicity screening.

Fabian Grimm

doi:10.14573/altex.1805301

Abstract

Assessing inter-individual variability in responses to xenobiotics remains a substantial challenge, both in drug development with respect to pharmaceuticals and in public health with respect to environmental chemicals. Although approaches exist to characterize pharmacokinetic variability, there are no methods to routinely address pharmacodynamic variability. In this study, we aimed to demonstrate the feasibility of characterizing inter-individual variability in a human in vitro model. Specifically, we hypothesized that genetic variability across a population of iPSC-derived cardiomyocytes translates into reproducible variability in both baseline phenotypes and drug responses. We measured baseline and drug-related effects in iPSC-derived cardiomyocytes from 27 healthy donors on kinetic Ca2+ flux and high-content live cell imaging. Cells were treated in concentration-response with cardiotoxic drugs: isoproterenol (β-adrenergic receptor agonist/positive inotrope), propranolol (β-adrenergic receptor antagonist/negative inotrope), and cisapride (hERG channel inhibitor/QT prolongation). Cells from four of the 27 donors were further evaluated in terms of baseline and treatment-related gene expression. Reproducibility of phenotypic responses was evaluated across batches and time. iPSC-derived cardiomyocytes exhibited reproducible donor-specific differences in baseline function and drug-induced effects. We demonstrate the feasibility of using a panel of population-based organotypic cells from healthy donors as an animal replacement experimental model. This model can be used to rapidly screen drugs and chemicals for inter-individual variability in cardiotoxicity. This approach demonstrates the feasibility of quantifying inter-individual variability in xenobiotic responses and can be expanded to other cell types for which in vitro populations can be derived from iPSCs.

Highlights

Inter-individual variability in responses to xenobiotics remains a substantial clinical and public health challenge
3.1 Reference chemicals are present in comparable free concentrations in cardiomyocyte media to those in human plasma All three test pharmaceuticals fully equilibrated within the rapid equilibrium dialysis (RED) device in the absence of proteins
3.2 induced pluripotent stem cells (iPSC)-derived cardiomyocytes exhibit reproducible inter-individual variability in baseline phenotypic characteristics iPSC-derived cardiomyocytes exhibited a range of donor-specific differences in their beating characteristics (Fig. 1A)

Summary

Introduction

Inter-individual variability in responses to xenobiotics remains a substantial clinical and public health challenge. For environmental toxicants, addressing inter-individual variability is necessary to ensure that exposure limits are protective of “typical” individuals, and of sensitive subpopulations (Zeise et al, 2013). Population-based in vitro-in vivo extrapolation (IVIVE) to address pharmacokinetic variability is an increasingly common step in safety evaluations for both pharmaceuticals and environmental chemicals (Bell et al, 2017; Wetmore, 2015). It is well-recognized that pharmacodynamic processes likely contribute if not more, to inter-individual variability (Turner et al, 2015; Zeise et al, 2013; Hattis and Lynch, 2007).

Objectives

Methods

Results

Conclusion