Computer-based prediction of the drug proarrhythmic effect: problems, issues, known and suspected challenges.

It is likely that computer modelling and simulations will become an element of comprehensive cardiac safety testing. Their role would be primarily the integration and the interpretation of previously gathered data. There are still unanswered questions and issues which we list and describe below. They include sources of data used for the development of the models as well as data utilized as input information, which can come from the in vitro studies and the quantitative structure-activity relationship models. The pharmacokinetics of the drugs in question play a crucial role as their active concentration should be considered, yet the question remains where is the right place to assess it. The pharmacodynamic angle includes complications coming from multiple drugs (i.e. active metabolites) acting in parallel as well as the type of interaction with (potentially) multiple affected channels. Once established, the model and the methodology of its use should be further validated, optimistically against individual data reported at the clinical level as the physiological, anatomical, and genetic parameters play a crucial role in the drug-triggered arrhythmia induction. All the abovementioned issues should be at least considered and-hopefully-resolved, to properly utilize the mathematical models for a cardiac safety assessment.