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COMBINING TRANSPORTER DATA WITH QUANTITATIVE SYSTEMS TOXICOLOGY MODELING (DILISYM) TO IMPACT DECISIONS IN DRUG DEVELOPMENT

A quantitative systems toxicology (QST) model of drug-induced liver injury (DILI) has been developed through the DILI-sim Initiative over the past 7 years to assist in the safety characterization of compounds in clinical development.  The emerging platform, DILIsym®, is capable of predicting and explaining hepatotoxicity due to bile acid transporter inhibition, mitochondrial dysfunction, oxidative stress, and lipotoxicity.  DILIsym includes interacting sub-models such as: a PBPK sub-model of drug disposition; a bile acid representation of homeostasis and disruption by transporter inhibition; a mitochondrial function and dysfunction sub-model including lipid metabolism and lipotoxicity; a sub-model of oxidative stress generation and clearance; a cell death representation of hepatocyte apoptosis, necrosis, and regeneration; and representations of many well-accepted and novel biomarkers of liver injury.