Quantitative Systems Toxicology Modeling of Otenaproxesul

This technical report presents a quantitative systems toxicology (QST) model developed for otenaproxesul, a drug designed to minimize gut toxicity while being an NSAID. The report outlines the methodology used to create a QST representation of otenaproxesul and its metabolites, including naproxen and H2S, within the DILIsym v8A framework. It explains how the model was utilized to interpret observed liver enzyme elevations in clinical studies, particularly in patients with fatty liver. The findings suggest that the observed ALT elevations are linked to the drug's mechanism of action, specifically the scavenging of reactive oxygen species (ROS) by H2S, which may lead to increased ROS levels upon cessation of the drug. The report also discusses the model's predictive capabilities regarding safe dosing regimens and identifies populations at risk for liver toxicity. The research was funded by Antibe Therapeutics and highlights the potential of QST modeling in understanding drug-induced liver injury.