A Bayesian Method for Population-wide Cardiotoxicity Hazard and Risk Characterization Using an In Vitro Human Model

Abstract

Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes are an established model for testing potential chemical hazards. Interindividual variability in toxicodynamic sensitivity has also been demonstrated in vitro; however, quantitative characterization of the population-wide variability has not been fully explored. We sought to develop a method to address this gap by combining a population-based iPSC-derived cardiomyocyte model with Bayesian concentration-response modeling. A total of 136 compounds, including 54 pharmaceuticals and 82 environmental chemicals, were tested in iPSC-derived cardiomyocytes from 43 nondiseased humans. Hierarchical Bayesian population concentration-response modeling was conducted for 5 phenotypes reflecting cardiomyocyte function or viability. Toxicodynamic variability was quantified through the derivation of chemical- and phenotype-specific variability factors. Toxicokinetic modeling was used for probabilistic in vitro-to-in vivo extrapolation to derive population-wide margins of safety for pharmaceuticals and margins of exposure for environmental chemicals. Pharmaceuticals were found to be active across all phenotypes. Over half of tested environmental chemicals showed activity in at least one phenotype, most commonly positive chronotropy. Toxicodynamic variability factor estimates for the functional phenotypes were greater than those for cell viability, usually exceeding the generally assumed default of approximately 3. Population variability-based margins of safety for pharmaceuticals were correctly predicted to be relatively narrow, including some below 10; however, margins of exposure for environmental chemicals, based on population exposure estimates, generally exceeded 1000, suggesting they pose little risk at current general population exposures even to sensitive subpopulations. Overall, this study demonstrates how a high-throughput, human population-based, in vitro-in silico model can be used to characterize toxicodynamic population variability in cardiotoxic risk.

Keywords: in vitro; drug; environmental chemical; population variability; toxicodynamic.