Improved Prediction of Drug-Induced Torsades de Pointes Through Simulations of Dynamics and Machine Learning Algorithms

Clin Pharmacol Ther. 2016 Oct;100(4):371-9. doi: 10.1002/cpt.367. Epub 2016 May 20.

Abstract

The ventricular arrhythmia Torsades de Pointes (TdP) is a common form of drug-induced cardiotoxicity, but prediction of this arrhythmia remains an unresolved issue in drug development. Current assays to evaluate arrhythmia risk are limited by poor specificity and a lack of mechanistic insight. We addressed this important unresolved issue through a novel computational approach that combined simulations of drug effects on dynamics with statistical analysis and machine-learning. Drugs that blocked multiple ion channels were simulated in ventricular myocyte models, and metrics computed from the action potential and intracellular (Ca(2+) ) waveform were used to construct classifiers that distinguished between arrhythmogenic and nonarrhythmogenic drugs. We found that: (1) these classifiers provide superior risk prediction; (2) drug-induced changes to both the action potential and intracellular (Ca(2+) ) influence risk; and (3) cardiac ion channels not typically assessed may significantly affect risk. Our algorithm demonstrates the value of systematic simulations in predicting pharmacological toxicity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Algorithms*
  • Humans
  • Machine Learning*
  • Risk Factors
  • Torsades de Pointes / chemically induced*