Key result
In silico models using the Cardiac Safety Simulator reproduced drug-induced arrhythmia effects (APD and QT prolongation, TdP) with less computational burden than published 3D simulations.
Single-cell-based in silico models can efficiently predict drug-induced proarrhythmic risk using in vitro electrophysiological data.
May enable efficient in silico arrhythmia prediction; leaves open clinical validation.
BACKGROUND AND PURPOSE: To determine the predictive performance of in silico models using drug-specific preclinical cardiac electrophysiology data to investigate drug-induced arrhythmia risk (e.g. Torsade de pointes (TdP)) in virtual human subjects. EXPERIMENTAL APPROACH: To assess drug proarrhythmic risk, we used a set of in vitro electrophysiological measurements describing ion channel inhibition triggered by the investigated drugs. The Cardiac Safety Simulator version 2.0 (CSS; Simcyp, Sheffield, UK) platform was used to simulate human left ventricular cardiac myocyte action potential models. RESULTS: This study shows the impact of drug concentration changes on particular ionic currents by using available experimental data. The simulation results display safety threshold according to drug concentration threshold and log (threshold concentration/ effective therapeutic plasma concentration (ETPC)). CONCLUSION AND IMPLICATIONS: We reproduced the underlying biophysical characteristics of cardiac cells resulted in effects of drugs associated with cardiac arrhythmias (action potential duration (APD) and QT prolongation and TdP) which were observed in published 3D simulations, yet with much less computational burden.
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Abbasi et al. (2016) studied Drug-induced arrhythmia risk. Cardiac Safety Simulator version 2.0 (in silico model) vs. Published 3D simulations was evaluated on Predictive performance for drug-induced arrhythmia risk. In silico models using the Cardiac Safety Simulator reproduced drug-induced arrhythmia effects (APD and QT prolongation, TdP) with less computational burden than published 3D simulations.
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