Systems biology in drug safety assessment: Use of a recalibrated hund-rudy model to predict the effect of novel drug compounds on action potential duration

摘要

Emerging practice in drug safety assessment delivers relatively early data on the potency of compounds at a range of cardiac ion channels, but there is little consensus on how to use this data to understand human risk, particularly when a compound modifies a range of mutually compensatory electrophysiological processes. In-silico physiological modelling of the processes involved offers a method to achieve this understanding but the models in the literature are not yet widely validated in the presence of a range of pharmacological profiles. We have used a model of canine ventricular myocytes and retrained it to data from a series of action potential (AP) recordings on isolated canine myocytes. By representing inter-animal variability by using an ensemble of parameters sets, we are able to evaluate the likely impact of novel compounds on a series of virtual dogs.