In silico predictions of drug-induced changes in human cardiac contractility align with experimental recordings

Drug-induced changes in cardiac contractility (inotropy) can lead to cardiotoxicity, a major cause of discontinuation in drug development. Preclinical approaches to assess cardiac inotropy are imperfect, with <i>in vitro</i> assays limited to stem cell-derived or adult human primary cardiomyocytes. Human mechanistic <i>in silico</i> modelling and simulations are already successfully applied for proarrhythmia prediction, contributing to cardiac safety assessment strategies in early drug development. In this study, we investigated their ability to predict drug-induced effects on cardiac inotropy. We considered a validation set of 28 neutral/negative inotropic and 13 positive inotropic reference compounds and simulated their effects on cell contractility via ion channel inhibition and perturbation of nine biomechanical modelling parameters, respectively. For each compound, a wide range of drug concentrations was simulated in an experimentally calibrated control population of 323 human ventricular <i>in silico</i> cells. Simulated biomarkers indicating drug-induced inotropic effects were compared with <i>in vitro</i> preclinical data from the literature. Computer simulations predicted drug-induced inotropic changes observed <i>in vitro</i> for 25 neutral/negative inotropes and 10 positive inotropes. Predictions of negative inotropic changes were quantitatively in agreement for 86% of tested drugs. Active tension peak was identified as the biomarker with highest predictive potential. This study describes the validation and application of an <i>in silico</i> cardiac electromechanical model for drug safety evaluation, combining ion channel inhibition data and information on potential inotropic mechanisms to predict inotropic changes. Furthermore, a route for its integration as part of a preclinical drug safety assessment strategy is outlined.