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 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.

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

“…Since 2005, it has become mandatory for all new drugs seeking regulatory approval to demonstrate that the IC 50 of the candidate drug for K v 11.1 is as distant as possible from the target of interest [ICH‐S7B, (ICH, 2005b)]. A 30‐fold separation margin was found to be highly predictive for hERG block in preclinical tests (Redfern et al , 2003); furthermore, clinical studies on healthy volunteers [ICH‐E14, Thorough QT/QTc Study (ICH, 2005a; Fermini et al , 2015)] must follow in vitro hERG tests for new drugs, and also be carried out for any other drugs that have undergone substantial alterations in formulation, administration route or target population (Shah, 2005). …”

Cardiac ion channels

“…94 Expert working groups are tasked with developing and testing detailed protocols for each of the 3 components, which will be validated by testing 29 established drugs spanning the range from low to high proarrhythmic liability. 95,96 Once established, CiPA may remove the need for expensive Thorough QT studies for most drug candidates.…”

Human ex-vivo action potential model for pro-arrhythmia risk assessment

“…Thus, our data suggest that the human ex-vivo AP-based model can potentially differentiate drugs with high versus low pro-arrhythmic risk based on the integrated electrophysiological effects (see also Vicente et al, 2015) providing more holistic insights into drug responses. The ability of APD90, triangulation and STV to respond differentially to perturbations introduced by pro-arrhythmic versus non-pro-arrhythmic drugs constituted a major critical finding of our investigation, although the confidence in the ability of our human ex-vivo AP-based model to identify drugs with pro-arrhythmic potential can be gradually grown by further evaluating drugs recently selected by the CiPA initiative (Fermini et al, 2016). In addition, the data we have generated with regard to the donor-to-donor variability indicate that the human heart-based approach can be implemented using a feasible number of donor samples, providing both a practical solution and affordable costs.…”

“…In a collaborative effort between FDA, Cardiac Safety Research Consortium, ILSI Health and Environmental Sciences Institute, Pharmaceutical Industry and Key Opinion Leaders, a new initiative has been launched which, is aimed at revising the QT paradigm and potentially eliminating the need for TQT studies. The CiPA (Comprehensive in vitro Pro-arrhythmia Assay) initiative is focused on updating the current cardiac safety testing paradigms and identifying a novel approach to better evaluate pro-arrhythmia risk, potentially removing the need for TQT studies and reducing the attrition of drugs that may benefit patients (Fermini et al, 2016;Gintant, Sager, & Stockbridge, 2016;Sager, Gintant, Turner, Pettit, & Stockbridge, 2014).…”