Developing cardiac electrophysiology models for drug safety studies

Simulations of the effect of multiple ion channel block on cardiac electrophysiology have become a key part of proposals to replace the ThoroughQT clinical study with more accurate preclinical tests. Success depends on having accurate mathematical models of both baseline cellular electrophysiology and drug-induced changes. Mathematical models include both ion channel kinetics (and drug effects on these) as well as action potential electrophysiology with appropriate expression levels of each ion channel type. We will extend and refine a new approach we have developed that uses shorter, more information-rich, experimental protocols for developing cell-specific mathematical models of ion channel and cellular electrophysiology, then predict drug responses with these models and validate against experiments. To make models that are ready for safety-critical use the problem of model selection (selecting the most appropriate set of equations) will also be addressed, as will model discrepancy – assessing, quantifying and predicting the difference between the model and reality. We will include uncertainty in our models and their inputs in a probabilistic framework, such that our predictions take the form of probability distributions. We will continue close collaboration with pharmaceutical companies and drug regulators to test and roll-out improved models.