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

Proarrhythmic cardiotoxicity remains a substantial barrier to drug development as well as a major global health challenge. In vitro human pluripotent stem cell-based new approach methodologies have been increasingly proposed and employed as alternatives to existing in vitro and in vivo 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 in vitro to in vivo therapeutic levels. This approach enabled the measurement of concentration responses and margins of exposure for two physiologically relevant metrics of proarrhythmic risk (i.e., action potential duration and triangulation assessed by optical mapping) across concentrations spanning three o..., , , # 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

Manuscript: [https://doi.org/10.1093/toxsci/kfae079](https://doi.org/10.1093/toxsci/kfae079)

Data: [https://doi.org/10.5061/dryad.sqv9s4nbn](https://doi.org/10.5061/dryad.sqv9s4nbn)

## Description of the data and file structure

**Data Collection:**

Engineered cardiac microtissues generated from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were loaded with the voltage sensitive dye, Di4-ANEPPS, and imaged at 37 degrees Celsius during 0.5 Hz field stimulation to record action potentials across a two-second interval. Action potentials were recorded for each microtissue across six half-log-spaced doses of one of four drugs (quinidine, cisapride, ranolazine, or verapamil) after 15-minute exposures as well as at baseline. For each action potential, action po...