Integrated and translational nonclinical in vivo cardiovascular risk assessment: Gaps and opportunities

Cardiovascular (CV) safety concerns are a significant source of drug development attrition in the pharmaceutical industry today. Though current nonclinical testing paradigms have largely prevented catastrophic CV events in Phase I studies, many challenges relating to the inability of current nonclinical safety testing strategies to model patient outcomes persist. Contemporary approaches include a spectrum of evaluations of CV structure and function in a variety of laboratory animal species. These approaches might be improved with a more holistic integration of these evaluations in repeat-dose studies, addition of novel endpoints with greater sensitivity and translational application, and use of more relevant animal models. Particular opportunities present with advances in imaging capabilities applicable to rodent and non-rodent species, technical capabilities for measuring CV function in repeat-dose animal studies, detection and quantitation of microRNAs and wider use of alternative animal models. Strategic application of these novel opportunities considering putative CV risk associated with the molecular drug target as well as inherent risks present in the target patient population could tailor or 'personalize' nonclinical safety assessment as a more translational evaluation.This paper is a call to action for the clinical and nonclinical drug safety communities to assess these opportunities to determine their utility in filling potential gaps in our current cardiovascular safety testing paradigms.

► Nonclinical CV safety testing paradigms may not adequately model complex patient populations. ► Holistic and predictive approach needed to understand long term nonclinical and clinical risks. ► Better understanding of concordance of animal models and clinical patients needed. ► Tools and technologies are available that could improve nonclinical modeling of clinical CV risk.