Modeling drug- and chemical-induced hepatotoxicity with systems biology approaches

author: Brett A. Howell, Hamner Institutes for Health Sciences
published: July 21, 2014,   recorded: May 2014,   views: 1515


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How can serious liver safety events be detected more efficiently and effectively in drug development? Can serious events we delineated from benign events? Could mechanistic modeling approaches help improve the detection and prevention of drug-induced liver injury?

A mechanistic, multi-scale, mathematical model is being developed through the DILI-sim Initiative to assist in the safety characterization of compounds in clinical development. The model is made available in the form of DILIsym® software. The primary goals for DILIsym® include understanding how in vitro toxicity assay results translate to in vivo scenarios, the relevance of pre-clinical results for humans, and how biomarker results translate to patient safety. The primary mechanistic areas of focus within the model include reactive oxygen/nitrogen species, mitochondrial dysfunction, and bile acid homeostasis and disruption.

Case studies will be presented demonstrating how drug metabolism and disposition intersect with hepatotoxicity, and how utilizing mechanistic modeling approaches incorporating this information allows for a better understanding of safety risks.

The integration of data and hypotheses about drug metabolism and disposition and hepatocellular injury into a mathematical model allowed for the holistic exploration of hepatotoxicity in animals and man.

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