EPA Science Inventory

Integrated and Translational Nonclinical In Vivo Cardiovascular Risk Assessment: Gaps and Opportunities

Citation:

Berridge, B. R., P. Hoffmann, J. Turk, F. Selike, G. Gintant, G. Hirkaler, K. L. DREHER, E. Schultz, D. Walker, N. Edmunds, W. Halpern, J. Falls, M. Sanders, S. Pettit, AND S. Pettit. Integrated and Translational Nonclinical In Vivo Cardiovascular Risk Assessment: Gaps and Opportunities. REGULATORY TOXICOLOGY AND PHARMACOLOGY. Elsevier Science Ltd, New York, NY, 12(S0273-2300):00186-9, (2012).

Description:

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 could 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 toxicogenomics, detection and quantitation of microRNAs, imaging capabilities applicable to rodent and non-rodent species, technical capabilities for measuring CVfunction in repeat-dose animal studies, 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 make progress on opportunities to fill gaps in our current cardiovascular safety testing paradigms. It is widely recognized in the drug development community that adverse cardiovascular (CV) effects plague the development of many novel pharmaceuticals and marketed drugs. These effects are often varied in their presentation, insidious in their onset and multi-factorial in their pathogenesis complicating their recognition in both nonclinical animal studies and in human patients. Accordingly, CV safety concerns are a major contributor to a debilitating drug development attrition challenging the pharmaceutical industry today.

Purpose/Objective:

review examines current drug cardiovascular toxicity testing methods; identifies their gaps responsible for drug pre and post market attrition; makes recommendations for new tests methods some of which may be translatable to CSS chemical cardiovascular testing.

URLs/Downloads:

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Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Start Date: 10/05/2012
Completion Date: 10/05/2012
Record Last Revised: 12/06/2012
Record Created: 10/08/2011
Record Released: 10/08/2011
OMB Category: Other
Record ID: 238809

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

ENVIRONMENTAL PUBLIC HEALTH DIVISION

CARDIOPULMONARY AND IMMUNOTOXICOLOGY BRANCH