Modelling and simulation for preclinical cardiac safety assessment of drugs with human iPSC-derived cardiomyocytes (Q2216529)

Since five years ago, regulators, industry and academia have been working to revise the paradigm of cardiac drug safety, which is based on a) human heart muscle cells, which can be largely obtained from donor stem cells, b) computer models of human heart electrophysiology both at the cellular and organ levels. It is possible that the combined use of in vitro and in silico human models during the preclinical phase will improve the specificity of proarrhythmic tests, and allow a better understanding of the need for close monitoring of the heart in the clinic and reduce animal experimentation. This review, based on the extensive literature, first briefly describes the mechanism of electrical activity in the human heart, its possible impairment due to drug side effects, and hiPSC-CM assays for testing the safety of cardiac drugs. The authors then provide a mathematical description of the electrophysiology of the human heart in terms of the mechanistic models of ODE and PDE and show how numerical analysis can provide insight into the genesis of drug-induced arrhythmias. They considered the following aspects of modelling: modelling and simulation of cardiac electrophysiology and arrhythmias; modelling of cardiac APs; nonlinear dynamics of ap models and cellular arrhythmias; modelling of ap wave propagation; modelling of cardiac arrhythmias at the PDE level; simulation based cardiac drug safety testing. The article concludes with an assessment of proarrhythmic risk. Although the classification of drugs by proarrhythmic risk, based on mechanistic models of electrophysiology of the human heart, is gaining acceptance in the pharmaceutical industry, there are still obstacles to its full integration into decision making. Some of these problems are listed by the authors. They are: validation, verification and uncertainty quantification; simulation based proarrhythmic risk assessment; modelling of hiPSC-cms; cardiac electro-mechanic coupling.