title: A New Perspective in the Field of Cardiac Safety Testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm.
abstract: For the past decade, cardiac safety screening to evaluate the propensity of drugs to produce QT interval prolongation and Torsades de Pointes (TdP) arrhythmia has been conducted according to ICH S7B and ICH E14 guidelines. Central to the existing approach are hERG channel assays and in vivo QT measurements. Although effective, the present paradigm carries a risk of unnecessary compound attrition and high cost, especially when considering costly thorough QT (TQT) studies conducted later in drug development. The C: omprehensive I: n Vitro P: roarrhythmia A: ssay (CiPA) initiative is a public-private collaboration with the aim of updating the existing cardiac safety testing paradigm to better evaluate arrhythmia risk and remove the need for TQT studies. It is hoped that CiPA will produce a standardized ion channel assay approach, incorporating defined tests against major cardiac ion channels, the results of which then inform evaluation of proarrhythmic actions in silico, using human ventricular action potential reconstructions. Results are then to be confirmed using human (stem cell-derived) cardiomyocytes. This perspective article reviews the rationale, progress of, and challenges for the CiPA initiative, if this new paradigm is to replace existing practice and, in time, lead to improved and widely accepted cardiac safety testing guidelines.
authors.affiliation: Global Safety Pharmacology, Pfizer Inc., Groton, CT, USA Bernard.fermini@pfizer.com.
authors.forename: Bernard
authors.initials: B
authors.lastname: Fermini
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
authors.affiliation: Translational Safety, Drug Safety and Metabolism, Innovative Medicines and Early Development, AstraZeneca R&D, Macclesfield, UK AnaBios Corporation, San Diego, CA, USA.
authors.forename: Najah
authors.initials: N
authors.lastname: Abi-Gerges
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Macclesfield, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bridgland-Taylor
authors.affiliation: Safety Assessment, GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: Khuram W
authors.initials: KW
authors.lastname: Chaudhary
authors.affiliation: Division of Applied Regulatory Science, CDER, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Colatsky
authors.affiliation: Safety Pharmacology Society, Reston, VA, USA.
authors.forename: Krystle
authors.initials: K
authors.lastname: Correll
authors.affiliation: Zenas Technologies LLC, New Orleans, LA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Crumb
authors.affiliation: Global Safety Pharmacology, Discovery Sciences, Janssen Research & Development LLC, Spring House, PA, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Damiano
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Inc, Cambridge, MA, USA.
authors.forename: Gul
authors.initials: G
authors.lastname: Erdemli
authors.affiliation: Department of Integrative Pharmacology, Integrated Sciences & Technology, AbbVie, North Chicago, IL, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Gintant
authors.affiliation: Department of Safety Assessment, Merck & Co, Kenilworth, NJ, USA.
authors.forename: John
authors.initials: J
authors.lastname: Imredy
authors.affiliation: Division of Cardiovascular and Renal Products, CDER, U.S. Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: John
authors.initials: J
authors.lastname: Koerner
authors.affiliation: ChanTest, A Charles River Company, Cleveland, OH, USA.
authors.forename: James
authors.initials: J
authors.lastname: Kramer
authors.affiliation: Bristol Myers Squibb Research & Development, Princeton, NJ, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Levesque
authors.affiliation: Division of Applied Regulatory Science, CDER, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.affiliation: Biolin Scientific, Ballerup, DK.
authors.forename: Anders
authors.initials: A
authors.lastname: Lindqvist
authors.affiliation: ChanTest, A Charles River Company, Cleveland, OH, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Obejero-Paz
authors.affiliation: Preclinical Safety, Sanofi, Bridgewater, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rampe
authors.affiliation: Global Cardiovascular Assessment, Eisai Co., Ltd., Ibaraki, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Sawada
authors.affiliation: Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Strauss
authors.affiliation: Victor Chang Cardiac Research Institute, St Vincent's Clinical School, University of NSW, Darlinghurst, NSW, Australia.
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Vandenberg
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis* / Q000209:etiology*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000175:diagnosis; D016171:Torsades de Pointes / Q000139:chemically induced / Q000175:diagnosis
keywords: CiPA; Comprehensive In Vitro Proarrhythmic Assay; ICH E14; ICH S7B; QT interval; hERG; safety