Data from: In vitro to in vivo extrapolation from three-dimensional hiPSC-derived cardiac microtissues and physiologically based pharmacokinetic modeling to inform next-generation arrythmia risk assessment

<p>Proarrhythmic cardiotoxicity remains a substantial barrier to drug development as well as a major global health challenge. <em>In vitro</em> human pluripotent stem cell-based new approach methodologies have been increasingly proposed and employed as alternatives to existing <em>in vitro</em> and <em>in vivo</em> models that do not accurately recapitulate human cardiac electrophysiology or cardiotoxicity risk. In this study, we expanded the capacity of our previously established three-dimensional human cardiac microtissue model to perform quantitative risk assessment by combining it with a physiologically based pharmacokinetic model, allowing a direct comparison of potentially harmful concentrations predicted <em>in vitro</em> to <em>in vivo</em> therapeutic levels. This approach enabled the measurement of concentration responses and margins of exposure for two physiologically relevant metrics of proarrhythmic risk (<em>i.e.</em>, action potential duration and triangulation assessed by optical mapping) across concentrations spanning three orders of magnitude. The combination of both metrics enabled accurate proarrhythmic risk assessment of four compounds with a range of known proarrhythmic risk profiles (<em>i.e., </em>quinidine, cisapride, ranolazine, and verapamil) and demonstrated close agreement with their known clinical effects. Action potential triangulation was found to be a more sensitive metric for predicting proarrhythmic risk associated with the primary mechanism of concern for pharmaceutical-induced fatal ventricular arrhythmias, delayed cardiac repolarization due to inhibition of the rapid delayed rectifier potassium channel, or hERG channel. This study advances human induced pluripotent stem cell-based three-dimensional cardiac tissue models as new approach methodologies that enable <em>in vitro</em> proarrhythmic risk assessment with high precision of quantitative metrics for understanding clinically relevant cardiotoxicity.</p>