General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy

Abstract

This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/ US Food and Drug Administration-sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate the progress in the development of a new cardiac safety paradigm, the Comprehensive in Vitro Proarrhythmia Assay (CiPA). The opinions regarding these principles reflect the collective views of those who participated in the discussion of this topic both at and after the breakout session. Although primarily discussed in the context of in silico models, these principles describe the interface between experimental input and model-based interpretation and are intended to be general enough to be applied to other types of nonclinical models for proarrhythmia assessment. This document was developed with the intention of providing a foundation for more consistency and harmonization in developing and validating different models for proarrhythmia risk prediction using the example of the CiPA paradigm.In July 2013, a Think Tank jointly sponsored by Cardiac Safety Research Consortium (CSRC), Health and Environmental Sciences Institute (HESI), and the US Food and Drug Administration (FDA) proposed a new cardiac safety paradigm, Comprehensive in Vitro Proarrhythmia Assay (CiPA). CiPA uses a new mechanistic, model-informed approach to predict the risk of Torsade de Pointes (TdP), a rare but potentially lethal form of ventricular tachycardia that can be induced by drugs and lead to sudden death. 1 Since its inception, global stakeholders including regulatory agencies (the FDA, European Medicines Agency, Health Canada, and the Japan Pharmaceuticals and Medical Devices Agency), industry, and academia have assembled various

Circadian rhythms of early afterdepolarizations and ventricular arrhythmias in a cardiomyocyte model

“…it gives few false negatives but false positives may be preventing safe drugs from entering the market [50]. The Comprehensive in vitro Pro-arrhythmia Assay (CiPA) is a new global initiative to create guidelines for the assessment of drug-induced TdP that recommends a central role for computational modeling of ion channels and in silico evaluation of compounds [19,40]. As noted above, many cardiac ion channels exhibit circadian oscillations, including ERG.…”

Real‐World Data and Physiologically‐Based Mechanistic Models for Precision Medicine

“…Alternatively, to validate such a patient-specific model, RWD with reliable clinical end points and patient-specific information is needed. The recent white paper from Li et al 10 discusses the strategy of how to build and validate such subpopulation CS models. In summary, to fully leverage physiologically based models and extend their impact, it is necessary to expand the underlying databases of physiological data and RWD sources can be highly useful for this purpose.…”

Beta-Adrenergic Receptor Stimulation Modulates the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin

“…To the best of our knowledge, previous experimental and observational studies of the potential proarrhythmic effects of CQ and AZM have not considered the role of beta-adrenergic receptor stimulation. Computational modeling has increasingly been used in cardiac safety pharmacology to predict the proarrhythmic effect of novel compounds (Qu et al, 2019;Li et al, 2020;Ridder et al, 2020). Therefore, this study aimed to assess the potential cellular proarrhythmic effects of CQ and AZM in both the absence and presence of beta-adrenergic receptor stimulation using a population of detailed in silico models of ventricular electrophysiology.…”