Presentation Description: Compound V is a small molecule with potential therapeutic benefits in patients with obesity. An early clinical safety trial produced two patients with liver enzyme elevations. This presentation discusses the combination of in vitro assays and in silico modeling to investigate the hepatotoxicity of Compound V. DILIsym, a quantitative systems toxicology (QST) model of drug-induced liver injury, was used to evaluate what mechanisms may be involved and if the compound concentration in the liver plays a role. Simulation results predict Compound V can injure hepatocytes and reveal the primary mechanism of injury: Reactive Oxidative Stress. This prediction of hepatotoxicity is highly sensitive to the value of the liver:blood partition coefficient (Kp). These results demonstrate the ability for QST modeling, specifically DILIsym, to propose plausible rationales for difficult-to-explain clinical liver toxicity data, and to suggest which further experiments would be most useful for understanding the underlying mechanisms of certain DILI cases.
Upon completion, participants will be able to recognize how in silico QST modeling and simulations identify data gaps, thereby guiding future in vitro experiments and in vivo studies.
Upon completion, participants will be able to design and execute a set of QST simulations to determine which mechanism(s) of injury is driven by a compound of interest.
Upon completion, participants will be able to identify and develop in vitro assays that are most useful for parameterizing a QST model like DILIsym.