An Integrated Panel of Assays for the Prediction of Drug-Induced Liver Injury

Abstract

Drug-induced liver injury (DILI) is a predominant reason for drug attritions, market withdrawals, and restricted use of drugs through black-box warnings. DILI is typically missed until late-stage discovery resulting in the costly termination of discovery programmes. Several publications have identified key molecular mechanisms that are said to contribute to DILI in man such as inhibition of the Bile Salt Export Pump (BSEP) and mitochondrial toxicity.

A combined testing approach in models that assessed these individual markers for hepatotoxicity would help improve the sensitivity and specificity of individual assays, and help improve the overall predictability of DILI during early drug discovery thus reducing early compound attritions. Here we present a strategy to integrate a matrix of assays of differing mechanistic pathways, developed for the assessment and ranking of potential DILI risk.