In silico assessment of drug safety in human heart applied to late sodium current blockers

摘要

Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (I-NaL) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K+ current (I-Kr). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of I-Kr/I-NaL ratio of steady-state block of drug candidates on torsadogenic biomarkers. The O'Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of I-NaL and I-Kr were evaluated. Safety plots were developed to illustrate the value of the specific biomarker for selected combinations of IC(50)s for I-Kr and I-NaL of potential drugs. The reference biomarkers at baseline changed depending on the drug specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of I-NaL) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle.