The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative — Update on progress

Abstract

The implementation of the ICH S7B and E14 guidelines has been successful in preventing the introduction of potentially torsadogenic drugs to the market, but it has also unduly constrained drug development by focusing on hERG block and QT prolongation as essential determinants of proarrhythmia risk. The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative was established to develop a new paradigm for assessing proarrhythmic risk, building on the emergence of new technologies and an expanded understanding of torsadogenic mechanisms beyond hERG block. An international multi-disciplinary team of regulatory, industry and academic scientists are working together to develop and validate a set of predominantly nonclinical assays and methods that eliminate the need for the thorough-QT study and enable a more precise prediction of clinical proarrhythmia risk. The CiPA effort is led by a Steering Team that provides guidance, expertise and oversight to the various working groups and includes partners from US FDA, HESI, CSRC, SPS, EMA, Health Canada, Japan NIHS, and PMDA. The working groups address the three pillars of CiPA that evaluate drug effects on: 1) human ventricular ionic channel currents in heterologous expression systems, 2) in silico integration of cellular electrophysiologic effects based on ionic current effects, the ion channel effects, and 3) fully integrated biological systems (stem-cell-derived cardiac myocytes and the human ECG). This article provides an update on the progress of the initiative towards its target date of December 2017 for completing validation.

Real Patient and its Virtual Twin: Application of Quantitative Systems Toxicology Modelling in the Cardiac Safety Assessment of Citalopram

“…Until recently, torsadogenicity assessments were typically focused on the inhibition of the cardiac I Kr current occurring at the level of the hERG channel (encoded by the human ether-a-go-go gene) (13)(14)(15)(16). Over the last few years, the comprehensive in vitro proarrythmia assay (CiPA) initiative has been advocating the in vitro assessment of multiple cardiac ion currents and the estimation of the combined effect of multiple ionic channel inhibition using cardiomyocyte cell-based quantitative systems models (17,18). However, the primary focus of the CiPA has been on the parent drug, specifically at the single cardiac cell level (19).…”

Disproportionality analysis of buprenorphine transdermal system and cardiac arrhythmia using FDA and WHO postmarketing reporting system data

“…Interestingly, increases in the QTc interval have been characterized to be highly sensitive but not very specific for predicting the risk of ventricular proarrhythmia. Currently efforts are ongoing to develop new assays to measure the proarrythmic risks of drugs in development [28,29].…”

A role for in vitro disease models in the landscape of preclinical cardiotoxicity and safety testing

“…Diabetes is strongly associated with cardiovascular diseases and symptoms including atrial fibrillation, atrial flutter, coronary artery disease and left ventricular hypertrophy [34] and can contribute to the development of diabetic cardiomyopathy [35]. Thus, the pathophysiological changes accompanying obesity and diabetes exert their effects both at the cellular and systemic levels resulting in cardiac dysfunction [23,36] Hence, the strategy of only examining the blockage of a single ion channel is increasingly being recognized as an imperfect measure ventricular repolarization [48,49].…”

“…Also, this much relied on in vitro assay for hERG, although highly sensitive, has only low specificity [49].…”

“…In the case of some drugs, these approaches have also resulted in false negative results, leading to drug attrition [50][51][52]. In order to address these issue, partnered efforts by multidisciplinary scientists, representing international regulatory groups, industry and academia are underway for the development of more newer approaches to assess proarrhythmic risk under the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiatives [49,53].…”