The DILIsym™ model and its application to hepatotoxicity testing in drug development

Drug induced liver injury (DILI) presents a substantial challenge to drug development, with DILI being responsible for multiple drugs being withdrawn from the market or receiving black box warnings at great cost. A mechanistic, multi-scale, mathematical model, DILIsym™, is being developed to assist in the safety characterization of compounds in in vitro to in vivo preclinical to first in human clinical development. Simulated humans, dogs, rats, and mice are included, with differences in biochemical variability amongst populations captured in SimPops™. The effects of reactive metabolites to elicit hepatotoxicity are included in v1A of the DILIsym™ model, with multiple drugs (e.g., acetaminophen) serving as exemplars for validation. Additional potential hepatotoxic participants, such as bile acids and mitochondria, are currently under development, broadening the range of compound types that can be evaluated with the model. Examples of how the DILIsym™ model can be used to support drug development safety assessment, experimental design, and increase understanding of DILI will be presented.