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

Apr 01, 2015 • By 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 Sawada, David G. Strauss, and Jamie I. Vandenberg

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 Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative is a publicprivate 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.

Introduction

On July 23, 2013, a think-tank meeting sponsored by the Cardiac Safety Research Consortium (CSRC), Health and Environmental Sciences Institute (HESI), and the US Food and Drug Administration (FDA) was held at the FDA headquarters in Silver Spring, Maryland, to discuss a novel approach to assess the proarrhythmic potential of drugs that prolong the QT interval. Prolongation of the QT interval is used as a surrogate marker for predicting the risk of a compound to induce a potentially fatal ventricular cardiac arrhythmia called Torsade de Pointes (TdP). However, the link between QT interval prolongation and TdP appears multifaceted and is influenced by a number of underlying factors including age, gender, underlying disease state, electrolyte imbalance, concomitant medication, and more.1,2 Although the majority of compounds that can induce TdP are known to inhibit cardiac potassium channels encoded by human-ether-à-go-go Related Gene (hERG),3–5 block of ionic current (IhERG) carried by recombinant hERG channels alone is not always predictive of delayed repolarization or proarrhythmic risks. For example, the L-type calcium channel blocker verapamil is a potent blocker of hERG current6 but does not prolong the QT interval or pose a risk of TdP.7 For small chemically manufactured molecules, the current preclinical (ICH S7B) and clinical (ICH E14) safety guidelines require first a preclinical electrophysiology test against hERG (or the native cardiac equivalent, the rapid delayed rectifier current IKr; known also as hERG) and an in vivo QT measurement followed, for drugs that pass preclinical testing, by a thorough QT (TQT) study.

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