Discussion

Drug-induced liver injury (DILI) is a major cause of attrition during drug development and drug withdrawal. Hence the need for predictive toxicology screening assays which enable early identification and deselection of compounds that have the potential to cause DILI. A novel and promising in vitro model is the 3D InSightTM primary human hepatocyte and non-parenchymal coculture model (hLiMT). In this study we assessed ATP depletion as an indicator of cytotoxicity towards the hLiMTs for marketed drugs reported to cause DILI, liver enzyme elevations or no reports of DILI in man. Test compounds were administered to the hLiMT on days 0, 5 and 9 and cytotoxicity was determined on days 5 and/or 14 using the ATP endpoint assay. The top concentration tested was ≥ 100 fold plasma Cmax or the limit of solubility. Biomarker release was assessed (alpha-Glutathione S Transferase, HMGB1 & miR122) in selected incubations.