Toward a correct understanding of the use of in silico models in cardiotoxicity assessment

Abstract

In drug discovery, it is very important to correctly assess cardiotoxicity in safety pharmacological evaluations. In particular, the ability to correctly evaluate the cardiotoxicity as to QT prolongation, likely to lead to fatal arrhythmias such as Torsade de Pointes, is considered to be of paramount importance. So far, in vitro and in vivo assessments of cardiotoxicity have been mainly performed, and myocardial cells and tissues with average electrophysiological properties are often employed in order to evaluate whether the average pharmacological effect is cardiotoxic or not. However, there is a paradox that drug-induced QT prolongation in real-world clinical practice often occurs only under special circumstances, such as transient diarrhea, hypothermia, and concomitant medications. In silico models of myocardial cells and tissues can arbitrarily change such input parameters, and might be a useful approach to view safety cardiotoxicity assessment not only as an average property but also as a zone of safety. In this talk, I would like to outline the desirable application of such in silico myocardial models in cardiotoxicity assessment.