Quantitative Systems Pharmacology Models for a New International Cardiac Safety Regulatory Paradigm: An Overview of the Comprehensive In Vitro Proarrhythmia Assay In Silico Modeling Approach

Abstract

As a relatively new discipline, quantitative systems pharmacology has seen a significant increase in the application and utility of drug development. One area that could greatly benefit from such an approach is in the proarrhythmia assessment of new drugs. The Comprehensive In Vitro Proarrhythmia Assay (Ci PA ) Initiative is a global public–private partnership project that has developed an integrated approach using mechanistic in silico models for proarrhythmia risk prediction. Progress to date has led to the formation of the International Council on Harmonisation Implementation Working Group to revise regulatory guidelines via the Questions‐and‐Answers process to address the best practices for proarrhythmia models and how they can impact clinical drug development. This article reviews the CiPA in silico model‐development process, focusing on its unique development and validation strategy, and summarizes the lessons learned as consideration points for the ongoing implementation of CiPA‐like in silico models in drug development.

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“…CiPA proposes to identify reliable proarrhythmia metrics by analyzing how drugs interact with a wide range of ionic channels, and by combining in vitro with in silico studies (Sager et al, 2014;Colatsky et al, 2016;Li et al, 2020). A multiscale in silico approach is adopted to evaluate the effect of channel blockade on the ventricular cardiomyocyte AP (Li et al, 2019). The in silico predictions are then validated in hiPSC-CMs.…”

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“…Platforms of hiPSC-CM to test drug safety by analyzing their proarrhythmic effects have been recently developed. Cardiac electrophysiology models have been applied more and more in the emerging discipline of quantitative system pharmacology (QSP) for cardiac safety prediction [112]. hiPSC-CMs have been applied in screening the proarrhythmic potential of drugs; Sotalol, Dofetilide, and E4031 for hERG channel blockade, Quinidine and Flecainide as sodium channel blockers, and Verapamil and Diltiazem as calcium channel inhibitors represent the main examples [113][114][115].…”

“…In particular, the potential torsadogenic effect of drugs is based on hERG (I Kr ) or I Ks (slow-delayed rectifier) outward currents inhibition with or without Nav1.5 (transient/late sodium currents, I Na /I NaL ) and Cav1.2 (L-Type Ca 2+ ) inward currents enhancement. The result is a delayed AP repolarization with increased incidence of early afterdepolarization (EADs), leading to ventricular arrhythmias such as TdP and ventricular fibrillation [112,[117][118][119]. Furthermore, a computational approach has been recently developed to recapitulate the human AP profile and drug-induced TdP [120][121][122].…”

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“…Furthermore, the funding agencies are playing an important role in the development of broad QSP capabilities in the academic sector and in enabling multistakeholder partnerships. Implementation of the Comprehensive In‐Vitro Proarrhythmia Assay initiative exemplifies a private‐public partnership for the goal of advancing QSP in drug development …”

“…Implementation of the Comprehensive In-Vitro Proarrhythmia Assay initiative exemplifies a private-public partnership for the goal of advancing QSP in drug development. 6 QSP has facilitated key decisions and transitions in drug discovery and development. Systems biology and systems pharmacology approaches of integrating big data across genetics, RNAs, transcription factors, proteomics, metabolomics, and chemicals (perturbagens) are the foundations for QSP.…”