Prevention of drug-induced liver injury (DILI) is a major objective of drug development, requiring substantial resources to screen compounds in preclinical studies. The DILIsym� model, a mechanistic, mathematical model of DILI, is being developed to facilitate the understanding of how in vitro toxicity assay results translate to pre-clinical animal models, the relevance of pre-clinical results for humans, and which emerging biomarkers are most translatable and informative for the clinic. The DILIsym� model was initially optimized and validated based on reactive metabolite-based hepatotoxicity, but has recently been expanded to include additional mechanisms such as direct mitochondria toxicity. Moreover, an additional, companion standalone model, MITOsym�, has been developed with the specific objective of translating in vitro mitochondria toxicity screening data into predictions of in vivo hepatotoxicity. The MITOsym� model includes the basic, essential biochemical pathways associated with cultured or primary hepatocyte respiration and bioenergetics (see diagram), and simulations recapitulate the dynamic changes in each in the presence of classic mitochondria toxins such as rotenone, FCCP, and oligomycin. The process of combining in vitro hepatocyte respiration preclinical data with the MITOsym� model, the DILIsym� model, and simulated compound exposure to predict in vivo hepatotoxicity will be described with examples. [2013 ACS abstract figure]

Using the DILIsym� and MITOsym� mathematical models to predict in vivo mitochondria-based DILI based on in vitro screening data

246th National Meeting (2013)

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