title: Early drug development: assessment of proarrhythmic risk and cardiovascular safety.
abstract: hERG assays and thorough ECG trials have been mandated since 2005 to evaluate the QT interval and potential proarrhythmic risk of new chemical entities. The high cost of these studies and the shortcomings inherent in these binary and limited approaches to drug evaluation have prompted regulators to search for more cost effective and mechanistic paradigms to assess drug liability as exemplified by the CiPA initiative and the exposure response ICH E14(R3) guidance document. Areas covered: This review profiles the changing regulatory landscape as it pertains to early drug development and outlines the analyses that can be performed to characterize preclinical and early clinical cardiovascular risk. Expert commentary: It is further acknowledged that the narrow focus on the QT interval needs to be expanded to include a more comprehensive evaluation of cardiovascular risk since unanticipated off target effects have led to the withdrawal of multiple drugs after they had been approved and marketed.
authors.affiliation: a Cardiovascular Safety Services , Celerion Inc. , Tempe , AZ , USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Lester
authors.affiliation: a Cardiovascular Safety Services , Celerion Inc. , Tempe , AZ , USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Olbertz
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006801:Humans; D009206:Myocardium / Q000378:metabolism
chemical_list: D051638:Ether-A-Go-Go Potassium Channels
keywords: ICH E14; ICH S7B; QT interval; Thorough QT; Torsades de pointes; cardiovascular safety; comprehensive in vitro proarrhythmia assay; exposure response modelling; hERG; proarrhythmia