Recent developments in using mechanistic cardiac modelling for drug safety evaluation

•Modelling and simulation can streamline decision making in drug safety testing.•Computational cardiac electrophysiology is a mature technology with a long heritage.•There are many challenges and opportunities in using in silico techniques in future.•We discuss how models can be used at different stages of drug discovery.•CiPA will combine screening platforms, human cell assays and in silico predictions. On the tenth anniversary of two key International Conference on Harmonisation (ICH) guidelines relating to cardiac proarrhythmic safety, an initiative aims to consider the implementation of a new paradigm that combines in vitro and in silico technologies to improve risk assessment. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative (co-sponsored by the Cardiac Safety Research Consortium, Health and Environmental Sciences Institute, Safety Pharmacology Society and FDA) is a bold and welcome step in using computational tools for regulatory decision making. This review compares and contrasts the state-of-the-art tools from empirical to mechanistic models of cardiac electrophysiology, and how they can and should be used in combination with experimental tests for compound decision making. In this article we present how in silico cardiac modelling has matured into a decision making tool in drug discovery, contrast the different approaches being proposed and show the opportunities and challenges that lie ahead for its acceptance by regulators.