Prediction of the Liver Toxicity of the Endothelin Receptor Antagonists Sitaxsentan and Ambrisentan for the Treatment of Pulmonary Arterial Hypertension with a Quantitative Systems Toxicology Tool (DILIsym)

Authors: Howell BA, Ferdous J, Siler SQ
Conference: SOT
Keywords: ambrisentan, liver toxicity, non-toxic compounds, pulmonary arterial hypertension, Quantitative Systems Toxicology (QST), sitaxsentan, toxic compounds
Software: DILIsym®
Division: Quantitative Systems Pharmacology (QSP)

Introduction

  • Sitaxsentan and ambrisentan are highly selective endothelin-1 type A receptor antagonists which were developed for the treatment of pulmonary arterial hypertension
  • Sitaxsentan was voluntarily withdrawn from the market due to concerns about liver toxicity, whereas ambrisentan is currently on the market
  • DILIsym, a mathematical framework of drug-induced liver toxicity, was used for quantitative system toxicology (QST) studies of the compounds
  • It is important to ensure that QST tools are capable of distinguishing between toxic and non-toxic compounds

Society of Toxicology 57th Annual Meeting and ToxExpo, March 11-15, 2018, San Antonio, Texas

By Brett A. Howell, Scott Q. Siler