Drug induced liver injury (DILI) is a leading cause of drug failure. It is reported that approx. 18% of all drug withdrawals from the market were attributed to DILI between 1953 and 20131. One worrying statistic is that only around 50% of compounds exhibiting human hepatic toxicities are picked up by preclinical animal studies2. To address the impact of this, it is essential to develop more human relevant models and apply these models earlier in the drug discovery process. However, these models need to be reliable and robust in the prediction of these toxicities.
Although there are some exceptions such as acetaminophen where the mechanism of DILI is well understood, generally, our mechanistic understanding of DILI-related adverse events is still lacking compared to other organ specific toxicities. One challenge in this respect is the fact that the adverse effect can be idiosyncratic where it is only observed in a small percentage of the population.
In a recent publication, Cyprotex addresses the complexities and challenges of DILI strategies, this can be accessed here.
Despite this, certain mechanistic endpoints have shown value in the prediction of DILI. These endpoints include:
More recently, advanced cell based models and sophisticated analytic techniques have been developed with enhanced predictive accuracy including:
Cyprotex are committed to research in the area of DILI to improve our understanding of the mechanisms behind this toxicity as well as enhance the detection of this liability early.
1 Onakpova IJ et al., (2016) Postmarketing withdrawal of 462 medicinal products because of adverse drug reactions: A systematic review of the world literature. BMC Medicine 14: 10
2 Olson H et al., (2000) Concordance of the toxicity of pharmaceuticals in human and in animals. Regul Toxicol Pharmacol 32(1): 56-67