title: Top-down, Bottom-up and Middle-out Strategies for Drug Cardiac Safety Assessment via Modeling and Simulations.
abstract: 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.
authors.affiliation: Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Cracow, Poland.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Tylutki
authors.affiliation: Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Cracow, Poland ; Simcyp Ltd. (part of Certara), Blades Enterprise Centre, S2 4SU Sheffield, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Polak
authors.affiliation: Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Cracow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wiśniowska
keywords: Drug safety; Modelling; Proarrhythmic effect; Simulation