Sex‐Specific Classification of Drug‐Induced Torsade de Pointes Susceptibility Using Cardiac Simulations and Machine Learning

Citations Over TimeTop 10% of 2021 papers

Abstract

Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a toxic side effect of many drugs. To assess TdP risk, safety regulatory guidelines require quantification of hERG channel block in vitro and QT interval prolongation in vivo for all new therapeutic compounds. Unfortunately, these have proven to be poor predictors of torsadogenic risk, and are likely to have prevented safe compounds from reaching clinical phases. Although this has stimulated numerous efforts to define new paradigms for cardiac safety, none of the recently developed strategies accounts for patient conditions. In particular, despite being a well-established independent risk factor for TdP, female sex is vastly under-represented in both basic research and clinical studies, and thus current TdP metrics are likely biased toward the male sex. Here, we apply statistical learning to synthetic data, generated by simulating drug effects on cardiac myocyte models capturing male and female electrophysiology, to develop new sex-specific classification frameworks for TdP risk. We show that (i) TdP classifiers require different features in females vs. males; (ii) male-based classifiers perform more poorly when applied to female data; and (iii) female-based classifier performance is largely unaffected by acute effects of hormones (i.e., during various phases of the menstrual cycle). Notably, when predicting TdP risk of intermediate drugs on female simulated data, male-biased predictive models consistently underestimate TdP risk in women. Therefore, we conclude that pipelines for preclinical cardiotoxicity risk assessment should consider sex as a key variable to avoid potentially life-threatening consequences for the female population.

Related Papers

• → Acquired QT interval prolongation and HERG: implications for drug discovery and development(2004)145 cited
• → Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea‐pig model(2008)75 cited
• → An Analysis of the Relationship Between Preclinical and Clinical QT Interval-Related Data(2017)56 cited
• → QT PRODACT: In Vivo QT Assay With a Conscious Monkey for Assessment of the Potential for Drug-Induced QT Interval Prolongation(2005)83 cited
• → In Vivo Effects of the IKr Agonist NS3623 on Cardiac Electrophysiology of the Guinea Pig(2008)32 cited