Summary

Toxicity has historically been a significant cause for compound attrition in drug development. This is unlikely to change in the near future. What can change is the timing of our decisions to terminate compounds due to toxicity, and the amount of time spent searching for compounds with adequate margins of safety. Toxicology biomarkers will play an increasingly important role in each of these opportunities.

Histology and clinical pathology in rodents form the core of non-clinical safety assessments, the majority of which are deployed during lead optimization. These measurements are of high quality, but they are time-consuming and resource-intensive. Innovative toxicology biomarkers can be used to improve our efficiency at prioritizing compounds for development by predicting chronic toxicities from shorter duration in vivo studies, and by driving the development of in vitro screens. A key challenge in reaching these objectives is identifying panels of predictive toxicology biomarkers.

In this chapter we demonstrated the use of toxicogenomics to identify a transcriptional biomarker of oval cell-mediated bile duct hyperplasia. Once identified, the specificity and sensitivity of the lead candidate biomarker, DMBT1, was evaluated in livers of rats treated with more than 30 different compounds comprising hepatotoxicities that ranged from BDH and hepatocyte proliferation, to phospholipidosis, hepatocellular vacuolation, apoptosis, and inflammation. Since its identification, DMBT1 has been used successfully as an early indicator of oval-cell mediated BDH in preclinical toxicology studies in vivo, and as a molecular endpoint to screen compounds for their ability to induce BDH in vitro. These successes are evidence that biomarkers such as DMBT1, combined with additional toxicology biomarkers being discovered using the strategies described in this chapter, as well as other methods, are tools that will increase the efficiency of the drug discovery process, through improved methods of drug candidate identification and development.

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