AUTHOR=Berridge Brian , Pierson Jennifer , Pettit Syril , Stockbridge Norman TITLE=Challenging the status quo: a framework for mechanistic and human-relevant cardiovascular safety screening JOURNAL=Frontiers in Toxicology VOLUME=6 YEAR=2024 URL=https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2024.1352783 DOI=10.3389/ftox.2024.1352783 ISSN=2673-3080 ABSTRACT=

Traditional approaches to preclinical drug safety assessment have generally protected human patients from unintended adverse effects. However, these assessments typically occur too late to make changes in the formulation or in phase 1 and beyond, are highly dependent on animal studies and have the potential to lead to the termination of useful drugs due to liabilities in animals that are not applicable in patients. Collectively, these elements come at great detriment to both patients and the drug development sector. This phenomenon is particularly problematic in the area of cardiovascular safety assessment where preclinical attrition is high. We believe that a more efficient and translational approach can be defined. A multi-tiered assessment that leverages our understanding of human cardiovascular biology, applies human cell-based in vitro characterizations of cardiovascular responses to insult, and incorporates computational models of pharmacokinetic relationships would enable earlier and more translational identification of human-relevant liabilities. While this will take time to develop, the ultimate goal would be to implement such assays both in the lead selection phase as well as through regulatory phases.