Idiosyncratic, drug-induced liver injury (IDILI) reactions, although typically rare, cause morbidity and death in patients. They also prompt lawsuits from harmed patients and are a common reason for withdrawal of drugs from the market or limitations on their use, thereby causing loss of investment and of profit for pharmaceutical companies. Current preclinical testing strategies fail to identify drugs with the potential to cause such adverse reactions. We have established a relatively simple, cell-based approach capable of classifying drugs according to their IDILI potential with remarkable selectivity and specificity. The resulting IDILI-ROC assay shows promise as a predictor of the likelihood that a drug candidate will cause a hepatocellular pattern of IDILI. Predictions based on the assay results could inform decisions about which candidates to move forward in the drug development process.

There is mounting evidence that the immune system is involved in IDILI reactions. Of potential importance in the hepatocellular killing that occurs is cytotoxic interaction of drugs with immune mediators such as tumor necrosis factor-alpha (TNF). In cultured hepatocytes, otherwise nontoxic concentrations of drugs associated with a hepatocellular pattern of DILI interact with these cytokines to cause cell death, and this interaction forms the basis for the assay (Maiuri et al., 2017).