Mechanism-Based Markers of Drug-Induced Liver Injury to Improve the Physiological Relevance and Predictivity ofIn VitroModels

Abstract

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 se...