Key result
Modeling and simulation approaches, including top-down, bottom-up, and middle-out strategies, are well-established tools for assessing drug proarrhythmic potency and improving cardiac safety prediction.
In silico modeling and simulation approaches are well-established and increasingly predictable tools for assessing drug proarrhythmic potency during development.
Cardiac safety is an issue causing early terminations at various stages of drug development. Efforts are put into the elimination of false negatives as well as false positives resulting from the current testing paradigm. In silico approaches offer mathematical system and data description from the ion current, through cardiomyocytes level, up to incorporation of inter-individual variability at the population level. The article aims to review three main modelling and simulation approaches, i.e. "top-down" which refers to models built on the observed data, "bottom-up", which stands for a mechanistic description of human physiology, and "middle-out" which combines both strategies. Modelling and simulation is a well-established tool in the assessment of drug proarrhythmic potency with an impact on research and development as well as on regulatory decisions, and it is certainly here to stay. What is more, the shift to systems biology and physiology-based models makes the cardiac effect more predictable.
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Tylutki et al. (2016) conducted a review in Drug-induced proarrhythmia. Modeling and simulation strategies (Top-down, Bottom-up, Middle-out) was evaluated. Modeling and simulation approaches, including top-down, bottom-up, and middle-out strategies, are well-established tools for assessing drug proarrhythmic potency and improving cardiac safety prediction.
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