Mechanism-Based Markers of Drug-Induced Liver Injury to Improve the Physiological Relevance and Predictivity of In Vitro Models

Abstract

It is evident from the drug development failures of the past 30 years that only through a better mechanistic understanding of specific drug-induced liver injury (DILI) will we improve our ability to predict clinical hepatotoxicity. Current in vitro models used for the prediction of DILI often suffer from uninformative, inappropriate, and poorly translatable endpoint measurements, and this may lead to unreliable inferences being drawn. Moreover, there is currently a significant disconnect between in vitro DILI endpoints and those used to assess hepatotoxicity in a clinical setting. This perspective article aims to identify the gaps in this area and reviews up-to-date information on current approaches to apply a human context to laboratory in vitro models. In order to develop better models to predict more accurately which chemicals will elicit hepatotoxicity in humans, a coordinated research effort is required involving the pharmaceutical industry, academia, and regulatory bodies. Key to this is selection and prioritization of endpoints of hepatocellular perturbation, as well as the definition of appropriate biomarkers, that truly reflect events occurring in the liver in vivo. We suggest that in order to improve our ability to explore mechanisms implicated in DILI, and thereby enhance the predictive power of in vitro test systems, there is an absolute need for better access to patient samples for use in exploratory biomarker development that better reflect specific mechanisms of hepatic injury, particularly those from industry-sponsored prospective clinical trials, and for improved phenotypic characterization of patients susceptible to DILI.