Ions, equations and electrons: the evolving role of computer simulations in cardiac electrophysiology safety evaluations

Reliable preclinical cardiac safety evaluations of drug candidates are essential for selecting the best therapeutic agents. Advanced automated patch clamp technologies now allow for characterizing drug effects on multiple cardiac currents, enabling subsequent simulations of integrated electrophysiological responses on cellular, tissue and organ levels. In this issue, Mirams et al. summarize the strengths and limitations of models and simulations predicting drug-induced electrophysiological responses, emphasizing delayed repolarization and Torsades de Pointes pro-arrhythmia. The utility of computational approaches is contingent upon realistic models of ventricular electrophysiology, robust characterization of drug-channel interactions and an understanding of channel-myocyte interactions and pro-arrhythmic mechanisms. Simulations evaluating effects on repolarization (hazard identification) should aid in selecting safer drug candidates early in drug discovery, while simulations evaluating risk of Torsades de Pointes (incorporating known risk factors) should quantify pro-arrhythmic risk and reduce the need for costly clinical QT studies later in development. The wider adoption of realistic models and simulation studies will depend on simulation performance compared with 'gold standard' clinical findings.