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

摘要

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 (CiPA) 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.