The utility of human iPS cell-derived cardiomyocytes in predicting the clinical risk of drugs that display discordance of cardiotoxicity by species

Abstract

Drug candidates sometimes cause a prolongation of the electrocardiogram QT-interval (QT) and torsades de pointes in humans, despite the fact that they do not cause them in non-rodent animals. Recent studies suggest that the cardiomyocytes derived from human induced-pluripotent stem cells (hiPS-CMs) are of sufficient quality to assess the cardiotoxicity of drugs in the preclinical setting. Thus, the usefulness of hiPS-CMs in correctly predicting the cardiotoxicity of drug candidates in the clinical setting, was examined using conventional drugs in the calcium transient analysis system FDSS/µCELL and the multielectrode array system MED64. The selection of the test drugs was based on previously reported studies. E-4031 and cisapride prolong the QT in humans, dogs and monkeys. Both drugs prolonged the calcium fluorescence peak width (PWD) in the FDSS/µCELL system and the field potential duration (FPD) in the MED64 system, both of which are thought to be surrogates of the QT. Diphenhydramine, famotidine and E-8010 prolong the QT in humans but not in dogs or monkeys. These drugs prolonged the PWD and FPD. On the other hand, verapamil and nifedipine prolong the QT in dogs or monkeys but not in humans. Both drugs shortened the PWD and FPD. These results suggest that the hiPS-CMs assay could correctly predict the QT effects in humans. The hiPS-CMs would be useful for predicting the effects of drug candidates on the QT of humans in preclinical in vitro studies.