Prediction of human cardiotoxic QT prolongation using in vitro multiple ion channel data and mathematical models of cardiac myocytes

Thousands of animals are used across the world for the assessment of cardiac toxicity each year. Animals are used at multiple stages of drug development, in every pharmaceutical company. This is primarily for detection of risk of Torsade-de-Pointes (TdP) cardiac arrhythmia. A leading cause of withdrawal of drugs from the market, TdP risk is one of the main causes of attrition during compound development. There are two major reasons that large numbers of animals have traditionally been required: first, there are a large number of potential drug interactions in the heart, which we could not hope to screen without a representation of all of the possible targets in the whole system (with an animal model); and second, the heart's electrophysiology has been considered "too complicated" to predict a drug effect―even given the full list of drug targets and affinities, the whole physiological system must be well represented (again, with an animal model).

Technological advances mean that neither of the points above should remain a stumbling block, and in this project we will reduce animal use by taking advantage of the following techniques: we will work with AstraZeneca and GlaxoSmithKline to assess compounds for multiple cardiac–ion-channel interactions, using high-throughput in vitro screens, to address the first point; mathematical models, quantifying the complex processes involved in generation of cardiac electrical activity, address the second. We will compare our predictions with the human trial results, statistically quantifying the level of predictive power that simulations have for human clinical trials. We will provide all of the generated data, simulation and analysis tools as open-source. There will therefore be no major obstacle to the widespread use of simulation, instead of animal models, for proarrhythmic screening, with additional benefits in terms of more accurate prediction of effects in human physiology.

• Engagement activities: Pint of Science 2014