A New Perspective in the Field of Cardiac Safety Testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm

Bernard Fermini, Jules C Hancox, Najah Abi-Gerges, Matthew Bridgland-Taylor, Khuram W Chaudhary, Thomas Colatsky, Krystle Correll, William Crumb, Bruce Damiano, Gul Erdemli, Gary Gintant, John Imredy, John Koerner, James Kramer, Paul Levesque, Zhihua Li, Anders Lindqvist, Carlos A Obejero-Paz, David Rampe, Kohei SawadaDavid G Strauss, Jamie I Vandenberg

Research output: Contribution to journalArticle (Academic Journal)peer-review

161 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalJournal of Biomolecular Screening
Volume21
Issue number1
Early online date13 Jul 2015
DOIs
Publication statusPublished - Jan 2016

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