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 around 50% of compounds that exhibit human hepatic toxicities are only picked up by preclinical animal studies². To address the impact of this, it is essential to develop more human relevant in vitro 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.

Evotec and wholly owned subsidiary Cyprotex have combined expertise in hepatotoxicity and DILI which spans from early discovery all the way through to the clinic. This way so we have a full picture of the entire drug discovery and development continuum, and so can support you at every stage of your project. Our scientific expertise and capabilities can be accessed as fee-for-services or as part of partially or fully integrated programs.

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, which can be accessed here.

Despite this, certain mechanistic endpoints have shown value in the prediction of DILI. These endpoints include:

• Mitochondrial dysfunction
  

• Reactive oxygen species (ROS)

• Oxidative stress

• GSH ROS MMP ATP Assay

• Cytochrome P450 time dependent inhibition

• Reactive metabolite formation and covalent binding

• Transporter interactions e.g. BSEP and MRP transporters

• Lysosomal trapping

• Phospholipidosis and steatosis

• Genotoxicity

More recently, advanced cell-based models and sophisticated analytic techniques have been developed with enhanced predictive accuracy including:

• 3D cell based hepatotoxicity models

• Cytotoxicity screening panel

• CellCiphr® Premier

• Transcriptomics analysis

Evotec and 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.