In silico modeling of methadone-related ion current effects to predict QT interval prolongation

Methadone is commonly associated with QT interval prolongation, which can lead to torsades de pointes. This effect has primarily been attributed to blockade of the delayed rectifier potassium current, I_Kr. However, methadone inhibits other ion currents to varying degrees. A deeper understanding of how ion currents interact to produce drug-induced QT interval prolongation may support development of strategies to mitigate risk of potentially fatal arrhythmias. Given the difficulty of isolating the contributions of specific ion currents in drugs with multiple effects, this study used cardiac electrophysiology simulations to predict current-specific effects of methadone-induced QT interval prolongation. Action potential (AP) and electrocardiogram (ECG) models based on the Tusscher-Noble-Noble-Panfilov (2004) model were built using the Cardiac Safety Simulator version 2.2. Single-cell APs were simulated using published in vitro data of methadone's effects (half-maximal inhibitory concentration and Hill coefficient) on multiple ion currents. The model was extrapolated to simulate ECGs using population parameters from a clinical study, and outputs from both models were compared to published data. A stepwise modeling approach isolated individual ion current contribution toward proarrhythmia. The final ECG model predicted heart rate-corrected QT intervals (QTc) within 1.5% of the observed data at four concentration ranges. Evaluation of individual ion currents toward QTc interval modulation suggested that I_Kr and I_K1 have a similar impact on methadone-related QTc interval prolongation. This study highlights the potential contribution of multiple ion currents to methadone's proarrhythmic effects and advances the understanding of ion current interplay underlying methadone-induced arrhythmia.