A compound attributes-based predictive model for drug induced liver injury in humans

PLoS One. 2020 Apr 15;15(4):e0231252. doi: 10.1371/journal.pone.0231252. eCollection 2020.

Abstract

Drug induced liver injury (DILI) is one of the key safety concerns in drug development. To assess the likelihood of drug candidates with potential adverse reactions of liver, we propose a compound attributes-based approach to predicting hepatobiliary disorders that are routinely reported to US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Specifically, we developed a support vector machine (SVM) model with recursive feature extraction, based on physicochemical and structural properties of compounds as model input. Cross validation demonstrates that the predictive model has a robust performance with averaged 70% of both sensitivity and specificity over 500 trials. An independent validation was performed on public benchmark drugs and the results suggest potential utility of our model for identifying safety alerts. This in silico approach, upon further validation, would ultimately be implemented, together with other in vitro safety assays, for screening compounds early in drug development.

MeSH terms

  • Chemical and Drug Induced Liver Injury*
  • Computer Simulation*
  • Databases, Factual
  • Forecasting
  • Humans
  • Liver / drug effects
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / classification
  • Sensitivity and Specificity
  • Support Vector Machine
  • Toxicity Tests / methods*
  • United States
  • United States Food and Drug Administration

Substances

  • Pharmaceutical Preparations

Grants and funding

The funder (Amgen Inc.) provided support in the form of salaries for authors [LY, GH, HYD] and the decision to publish, but did not have any additional role in the study design, data collection and analysis, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.