title: Evolution of strategies to improve preclinical cardiac safety testing.
abstract: The early and efficient assessment of cardiac safety liabilities is essential to confidently advance novel drug candidates. This article discusses evolving mechanistically based preclinical strategies for detecting drug-induced electrophysiological and structural cardiotoxicity using in vitro human ion channel assays, human-based in silico reconstructions and human stem cell-derived cardiomyocytes. These strategies represent a paradigm shift from current approaches, which rely on simplistic in vitro assays that measure blockade of the Kv11.1 current (also known as the hERG current or IKr) and on the use of non-human cells or tissues. These new strategies have the potential to improve sensitivity and specificity in the early detection of genuine cardiotoxicity risks, thereby reducing the likelihood of mistakenly discarding viable drug candidates and speeding the progression of worthy drugs into clinical trials.
authors.affiliation: Department of Integrative Pharmacology, Integrated Science and Technology, AbbVie, Department ZR 13, Building AP9 01, 1 North Waukegan Road, North Chicago, Illinois 60064-6118, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Gintant
authors.affiliation: Stanford University, 719 Carolina Street, San Francisco, California 94107, USA.
authors.forename: Philip T
authors.initials: PT
authors.lastname: Sager
authors.affiliation: Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993, USA.
authors.forename: Norman
authors.initials: N
authors.lastname: Stockbridge
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D066126:Cardiotoxicity / Q000175:diagnosis* / Q000378:metabolism; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D018570:Risk Assessment; D012449:Safety
chemical_list: D002121:Calcium Channel Blockers; D007473:Ion Channels