title: Integrated and translational nonclinical in vivo cardiovascular risk assessment: gaps and opportunities.
abstract: 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.
authors.affiliation: GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Berridge
authors.forename: Peter
authors.initials: P
authors.lastname: Hoffmann
authors.forename: James R
authors.initials: JR
authors.lastname: Turk
authors.forename: Frank
authors.initials: F
authors.lastname: Sellke
authors.forename: Gary
authors.initials: G
authors.lastname: Gintant
authors.forename: Gerald
authors.initials: G
authors.lastname: Hirkaler
authors.forename: Kevin
authors.initials: K
authors.lastname: Dreher
authors.forename: A Eric
authors.initials: AE
authors.lastname: Schultze
authors.forename: Dana
authors.initials: D
authors.lastname: Walker
authors.forename: Nick
authors.initials: N
authors.lastname: Edmunds
authors.forename: Wendy
authors.initials: W
authors.lastname: Halpern
authors.forename: James
authors.initials: J
authors.lastname: Falls
authors.forename: Marty
authors.initials: M
authors.lastname: Sanders
authors.forename: Syril D
authors.initials: SD
authors.lastname: Pettit
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D004195:Disease Models, Animal; D015195:Drug Design; D004345:Drug Industry / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D023381:Endpoint Determination; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D012107:Research Design; D018570:Risk Assessment / Q000379:methods; D013045:Species Specificity
chemical_list: D035683:MicroRNAs