Information-Derived Mechanistic Hypotheses for Structural Cardiotoxicity

Chem Res Toxicol. 2018 Nov 19;31(11):1119-1127. doi: 10.1021/acs.chemrestox.8b00159. Epub 2018 Oct 17.

Abstract

Adverse events resulting from drug therapy can be a cause of drug withdrawal, reduced and or restricted clinical use, as well as a major economic burden for society. To increase the safety of new drugs, there is a need to better understand the mechanisms causing the adverse events. One way to derive new mechanistic hypotheses is by linking data on drug adverse events with the drugs' biological targets. In this study, we have used data mining techniques and mutual information statistical approaches to find associations between reported adverse events collected from the FDA Adverse Event Reporting System and assay outcomes from ToxCast, with the aim to generate mechanistic hypotheses related to structural cardiotoxicity (morphological damage to cardiomyocytes and/or loss of viability). Our workflow identified 22 adverse event-assay outcome associations. From these associations, 10 implicated targets could be substantiated with evidence from previous studies reported in the literature. For two of the identified targets, we also describe a more detailed mechanism, forming putative adverse outcome pathways associated with structural cardiotoxicity. Our study also highlights the difficulties deriving these type of associations from the very limited amount of data available.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adverse Drug Reaction Reporting Systems
  • Animals
  • Data Mining
  • Databases, Factual
  • Drug-Related Side Effects and Adverse Reactions*
  • Heart Diseases / chemically induced*
  • Humans
  • Models, Theoretical*
  • United States
  • United States Food and Drug Administration