Abstract

The liver is one of the organs most susceptible to drug toxicity and drug-inducedliver injury (DILI). DILI is a major cause of drug attrition, with more than 750 FDAapproved drugs known to have a degree of DILI risk [1]. There are a number ofstrategies to de-risk DILI in drug discovery and, in recent years, focus has turned tohuman in vitro 3D liver models to better predict DILI in early and pre-clinicaldevelopment [2]. These models culture primary human liver cells, often in cocultures,in a physiologically relevant environment allowing them to stay functionalfor extended periods of time.Here, we assessed whether a microphysiological system (MPS), also known asOrgan-on-a-Chip (OOC), in vitro liver model could be used to understand thedetailed mechanistic aspects of liver toxicity. The MPS has previous been shown tomaintain highly functional 3D liver microtissues, under flow, for up to 4 weeks [3],potentially making it highly suited to assessing DILI. We used two antidiabeticthiazolidinediones, troglitazone (was market approved and later removed due toDILI) and pioglitazone (approved medicine but with known DILI risk) to assesswhether the MPS can detect acute and chronic toxicity. DILI by both of thesecompounds is typically difficult to detect using standard in vitro liver assays and invivo pre-clinical models [4]. For each compound, a range of functional liver-specificendpoints were analysed (inc. clinical biomarkers) across a concentration responseto generate EC50 curves. Functional liver-specific endpoints were analysed to createa distinct mechanistic “signature of hepatotoxicity” from the MPS to demonstrate itscapacity to assess human DILI risk of novel agents.