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Sex-Specific Classification of Drug-Induced Torsade de Pointes Susceptibility Using Cardiac Simulations and Machine Learning
- Source :
- Clinical pharmacology and therapeutics, vol 110, iss 2, Clin Pharmacol Ther
- Publication Year :
- 2021
- Publisher :
- eScholarship, University of California, 2021.
-
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. While 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 underrepresented 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 (1) TdP classifiers require different features in females vs. males; (2) malebased classifiers perform more poorly when applied to female data; (3) 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 lifethreatening consequences for the female population.
- Subjects :
- Acute effects
Drug
Calcium Isotopes
Male
Side effect
media_common.quotation_subject
hERG
Bioinformatics
Cardiovascular
030226 pharmacology & pharmacy
QT interval
Models, Biological
Risk Assessment
Article
Machine Learning
03 medical and health sciences
0302 clinical medicine
Text mining
Sex Factors
Torsades de Pointes
Risk Factors
Models
Medicine
Humans
Pharmacology (medical)
Myocytes, Cardiac
Computer Simulation
Pharmacology & Pharmacy
Risk factor
media_common
Pharmacology
Cardiotoxicity
Myocytes
biology
Statistical learning
business.industry
Prevention
Pharmacology and Pharmaceutical Sciences
Biological
Sex specific
Heart Disease
5.1 Pharmaceuticals
030220 oncology & carcinogenesis
biology.protein
Female
Development of treatments and therapeutic interventions
business
Risk assessment
Cardiac
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Clinical pharmacology and therapeutics, vol 110, iss 2, Clin Pharmacol Ther
- Accession number :
- edsair.doi.dedup.....d91b7c691f7e2c5baf9592b6184ebdcb