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.
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Johnstone RH, Chang ET, Bardenet R, de Boer TP, Gavaghan DJ, Pathmanathan P, Clayton RH, Mirams GR (2016). Uncertainty and variability in models of the cardiac action potential: Can we build trustworthy models? J Mol Cell Cardiol 96: 49-62. doi: 10.1016/j.yjmcc.2015.11.018.
Williams G, Mirams GR (2015). A web portal for in-silico action potential predictions. J Pharmacol Toxicol Methods 75: 10-6. doi: 10.1016/j.vascn.2015.05.002.
Cooper J, Spiteri RJ, Mirams GR (2015). Cellular cardiac electrophysiology modeling with Chaste and CellML. Front Physiol 5:511. doi: 10.3389/fphys.2014.00511.
Mirams GR, Davies MR, Brough SJ, Bridgland-Taylor MH, Cui Y, Gavaghan DJ, Abi-Gerges N (2014) Prediction of Thorough QT study results using action potential simulations based on ion channel screens. J Pharmacol Toxicol Methods pii: S1056-8719(14)00235-4. doi: 10.1016/j.vascn.2014.07.002.
Beattie KA, Luscombe C, Williams G, Munoz-Muriedas J, Gavaghan DJ, Cui Y, Mirams GR (2013) Evaluation of an in silico cardiac safety assay: using ion channel screening data to predict QTinterval changes in the rabbit ventricular wedge. J Pharmacol Toxicol Methods 68(1):88-96. doi: 10.1016/j.vascn.2013.04.004.
Elkins RC, Davies MR, Brough SJ, Gavaghan DJ, Cui Y, Abi-Gerges N, Mirams GR (2013) Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment. J Pharmacol Toxicol Methods 68(1):112-22. doi: 10.1016/j.vascn.2013.04.007.
Principal investigatorDr Gary Mirams
InstitutionUniversity of Oxford
Co-InvestigatorProfessor David Gavaghan
Dr Blanca Rodriguez
Professor Denis Noble