Application of Retrospective Models

The works of Diaz et al. (2013), Tarrant et al. (2015), Uppal et al. (2015), and Zabka et al. (2015) are recent examples of utilizing cell-based models to investigate toxicity observed in animal or clinical studies and to evaluate the in vitro to in vivo translation and cross species sensitivity to an identified toxicant. 

Safety lead optimization efforts are used to maximize resources and early decision-making for the purposes of reducing costs and animal use and removing the least favorable compounds early during the discovery phase, when there is most flexibility in optimizing the candidate molecule. The ultimate goal is to identify a lead development candidate that has the most superior safety characteristics and, for those safety issues identified, a well-characterized risk assessment to reduce clinical attrition due to toxicity and inform the clinical development plan. 

To that end, the components of (he safety lead optimization strategy should include (i) a TSA to evaluate potential target-related issues and therapeutic area considerations, 

Finally, for such a strategy to woik, there needs to be a cross functional culture that embraces the inclusion of safety lead optimization sfiategies and approaches as part of the hoUstic assessment and identification of candidate molecules during the dmg discovery phase this includes engagement of chemists, pharmacologists, DMPK, and pharmaceutics scientists, as well as an understanding of how safety scientists utilize the data to build a weight-of-evidence approach for safety assessment. 

Potter, D.M., Will, Y. (2014). Human drug-induced liver injury severity is highly associated with dual inhibition of mitochondrial function and bile salt export pump. Hepatology, 60,1015-1022. 

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