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Review
. 2024 Mar 25:6:1352783.
doi: 10.3389/ftox.2024.1352783. eCollection 2024.

Challenging the status quo: a framework for mechanistic and human-relevant cardiovascular safety screening

Brian Berridge  1 , Jennifer Pierson  2 , Syril Pettit  2 , Norman Stockbridge  3
Affiliations
Review

Challenging the status quo: a framework for mechanistic and human-relevant cardiovascular safety screening

Brian Berridge et al. Front Toxicol. .

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.

Keywords: cardiac; cardiac NAM; cardiac drug development; cardiac toxicity; cardiovascular toxicity.

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Conflict of interest statement

Author BB was employed by B2 Pathology Solutions, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Drug discovery process. Note. A novel human-relevant and mechanistic screening paradigm positioned earlier in development would enable evidence-based lead selection and more informed preclinical and clinical safety assessments.
FIGURE 2
FIGURE 2
Tiered approach for human CV safety assessment. Note. A human-relevant and mechanistically-based screening strategy could include an initial screen for bioactivities of CV concern. The outcomes of subsequent and qualifying in vitro systems within a framework of recognized CV “failure modes” could be computationally extrapolated to human-relevant exposures. Actionable decisions include approaches to molecular design, a more informed candidate selection and bespoke clinical trial design.
FIGURE 3
FIGURE 3
Value propositions for an earlier integration of a human-relevant and mechanistic screening strategy.
See this image and copyright information in PMC

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