A new assessment tool that facilitates the prediction of the proarrhythmic risk of a wide range of drugs without carrying out time-consuming simulations during preclinical screening.
Arrhythmogenic indices like Tx (drug concentration leading to a 10% prolongation of the action potential over the effective free therapeutic plasma concentration), TqNet (net charge carried by ionic currents when exposed to 10 times the effective free therapeutic plasma concentration ) and Ttriang (triangulation for a drug concentration of 10 times the effective free therapeutic plasma concentration over triangulation in control) were precomputed for a large combination of currents block values with respect to the 3-current combinations IKr, ICaL, IKs and IKr, ICaL, INaL .
Power of prediction was enhanced by combining Tx, TqNet and Ttriang for the two combinations in one classifier based on decision trees achieving a classification accuracy of 94.5% for a dataset of 109 drugs of known torsadogenic risk (51 positive). This TdP risk classification can be as accurate as when considering effects on the seven main ion currents proposed by the CiPA initiative.
QT/TdP Risk Screen is a ready-to-use tool based on more than 450 000 simulations, which can be easily employed to quickly assess the proarrhythmic risk of libraries of compounds.