Erdemli, Gul, Fermini, Bernard, Hancox, Jules C. , Abi-Gerges, Najah, Bridgland-Taylor, Mark, Chaudray, Khuram, Colatsky, Thomas, Correll, Krystle, Crumb, William, Damiano, Bruce, Gintant, Gary, Imredy, John, Koerner, John, Kramer, James, Leishman, Derek, Levesque, Paul , Li, Zhihua, Lindqvist, Andrew, Obejero-Paz, Carlos, Sawada, Kowei, Strauss, David, Vandenberg, Jamie and Vargas, Hugo (2015) Next generation cardiac safety testing through the Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm. Journal of Biomolecular Screening, 21 (1). pp. 1-11. ISSN 1087-05711552-454X

Abstract

For the last 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 the ICH-S7B and ICH-E14 guidelines. hERG channel assays and in vivo QT measurements have been central to the existing approach. While effective, the present paradigm carries a risk of unnecessary compound attrition and high cost, especially when “thorough QT” (TQT) studies are initiated. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is a public-private collaboration with the aim of updating the existing cardiac safety testing paradigm in order to better evaluate arrhythmia risk and remove the need for TQT testing. 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 models. These results are then to be validated using human (stem-cell derived) cardiomyocytes. This article reviews the rationale, progress of and challenges for the CiPA initiative, if this new paradigm to replace existing practice and, in time, lead to updated and widely accepted cardiac safety testing guidelines.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	04 Jul 2016 23:45
URI:	https://oak.novartis.com/id/eprint/25556