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Jun 20, 2020

DILIsym: Quantitative systems toxicology impacting drug development

Abstract

DILIsym®, a quantitative systems toxicology model developed over the last decade by the drug-induced liver injury (DILI)-sim Initiative, has provided novel insights regarding mechanisms underlying drug-induced liver injury and why animal models sometimes fail to accurately assess the liver safety liability of new drug candidates. For example, DILIsym, but not routine preclinical testing, predicted the human hepatotoxicity of the migraine drugs telcagepant and MK3207 that terminated their clinical development. DILIsym also predicted that the next in-class drug, ubrogepant, would be relatively safe for the liver; this prediction was prospectively confirmed in phase-3 clinical trials leading to FDA approval without liver safety warnings. DILIsym also identifies mechanisms underlying liver toxicity, and this information can identify patient-specific risk factors for drug-induced liver injury including drug–drug interactions and certain disease states, improving risk management and pharmacovigilance. DILIsym provides an example of how increased application of quantitative systems toxicology modeling should lead to more efficient development of new drugs.

By Paul B Watkins

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