title: Recent developments in the science of proarrhythmic cardiac safety of new drugs.
abstract: Following marketing withdrawals of several drugs due to proarrhythmic safety concerns, the ICH Guidelines S7B and E14 were released in 2005 and have guided pre-approval cardiac safety assessments in multiple regulatory jurisdictions. While this S7B-E14 paradigm has successfully prevented drugs with unanticipated potential for inducing Torsades de Pointes entering the market, it has unintentionally resulted in the termination of development programs for potentially important compounds that could have exhibited a favourable benefit-risk balance. The Comprehensive In vitro Proarrhythmia Assay paradigm is currently attracting considerable attention as a solution to this problem. While much evaluative work in this new paradigm will be conducted in the non-clinical domain, human electrocardiographic assessments will remain an important component of the overall investigational strategy, possibly being conducted in Phase I trials employing exposure-response modelling. This article reviews recent developments in proarrhythmic cardiac safety assessments of new drugs, their rationales, and current limitations.
authors.affiliation: Cardiac Safety Services, QuintilesIMS, 4820 Emperor Blvd, Durham, NC 27703, USA.
authors.forename: J Rick
authors.initials: JR
authors.lastname: Turner
authors.affiliation: Cardiac Safety Services, QuintilesIMS, 602 Western Express Highway, Andheri East, Mumbai 400 069, Maharashtra, India.
authors.forename: Dilip R
authors.initials: DR
authors.lastname: Karnad
authors.affiliation: Customer Solutions Management Group, QuintilesIMS, 4820 Emperor Blvd, Durham NC 27703, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Cabell
authors.affiliation: Cardiac Safety Services, Global Head, Cardiac Safety Center of Excellence, QuintilesIMS, 602 Western Express Highway, Andheri East, Mumbai 400 069, Maharashtra, India.
authors.forename: Snehal
authors.initials: S
authors.lastname: Kothari
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D004341:Drug Evaluation / Q000379:methods*; D006801:Humans; D016896:Treatment Outcome
chemical_list: D000889:Anti-Arrhythmia Agents
keywords: Brugada syndrome; Exposure-response modelling; Human induced pluripotent stem-cell derived cardiomyocytes ; In silico modelling; Short QT syndrome; T-wave morphology; Thorough QT/QTc study; Torsades de Pointes; Tpe 