ArticleProgress in biophysics and molecular biology2019
Predicting critical drug concentrations and torsadogenic risk using a multiscale exposure-response simulator.
Article in Progress in biophysics and molecular biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 11 citations in OpenAlex.
- Sex Differences in Drug-Induced Arrhythmogenesis.Frontiers in physiology · 2021Article
- Classifying Drugs by their Arrhythmogenic Risk Using Machine Learning.Biophysical journal · 2020Article
- General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy.Clinical pharmacology and therapeutics · 2020Article
- Machine learning in drug development: Characterizing the effect of 30 drugs on the QT interval using Gaussian process regression, sensitivity analysis, and uncertainty quantification.Computer methods in applied mechanics and engineering · 2019Article
- Three-Dimensional Heart Model-Based Screening of Proarrhythmic Potential byFrontiers in physiology · 2019Article
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
Torsades de pointes is a serious side effect of many drugs that can trigger sudden cardiac death, even in patients with structurally normal hearts. Torsadogenic risk has traditionally been correlated with the blockage of a specific potassium channel and a prolonged recovery period in the electrocardiogram. However, the precise mechanisms by which single channel block translates into heart rhythm disorders remain incompletely understood. Here we establish a multiscale exposure-response simulator that converts block-concentration characteristics from single cell recordings into three-dimensional excitation profiles and electrocardiograms to rapidly assess torsadogenic risk. For the drug dofetilide, we characterize the QT interval and heart rate at different drug concentrations and identify the critical concentration at the onset of torsades de pointes: For dofetilide concentrations of 2x, 3x, and 4x, as multiples of the free plasma concentration C
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