Host: The Japanese Society of Toxicology
Name : The 47th Annual Meeting of the Japanese Society of Toxicology
Date : 2020 -
During the early stages of the drug discovery process, the primary focus of drug design is the development of target efficacy and optimization of PK/PD properties. Consequently, the integration and application of safety data during these stages may not be prioritized. If we are to reduce the chance of drug attrition due to safety, however, it is important to proactively mitigate safety signals at this stage. In order to achieve this, it is important that any in vitro assay is validated and demonstrated to have some correlation with human safety and ‘added value’ with respect to assays that have already been established. It has been learnt that the traditional validation datasets of new assays, which often include toxicologically potent drugs such as doxorubicin, cisplatin and sunitinb, can be useful in that they provide information on the dynamic range of an assay and translation to human safety. These compounds by themselves, however, may not provide enough evidence to warrant the consideration of the assay in early drug design. In order to influence drug design, in vitro assays should be validated using test sets that are mechanistically relevant to the toxicological endpoint being modeled and are applicable to modern chemical space. Evidence that the assay can differentiate structural analogues with different toxicological profiles, thus reflecting the situation that is often encountered in early drug discovery, would be advantageous. Through the review of in vitro data for the prediction of bone marrow toxicity and hepatotoxicity, it will be shown that structure-based validation studies can provide valuable evidence that can drive the ‘Safety By Design’ concept and the development of cost-effective, risk assessment strategies. Current early safety screening strategies will also be discussed along with their application to small molecule projects.
