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Precliical Safety Biomarkers for Drug-Induced Vascular Injury-Current Status and blueprint for the Future

Hoffmann, Peter (2014) Precliical Safety Biomarkers for Drug-Induced Vascular Injury-Current Status and blueprint for the Future. Toxicologic Pathology, 42 (4). pp. 635-657. ISSN 0192-6233


Better biomarkers are needed to identify, characterize, and/ormonitor drug-induced vascular injury (DIVI) in nonclinical species and patients. The PredictiveSafetyTestingConsortium(
PSTC), a precompetitive collaboration of pharmaceutical companies and theU.S.Food andDrugAdministration (FDA),
formed theVascular InjuryWorkingGroup (VIWG) to develop and qualify translatable biomarkers ofDIVI. TheVIWGfocused its research on acuteDIVI
because early detection for clinical and nonclinical safety monitoring is desirable. TheVIWG developed a strategy based on the premise that biomarkers of
DIVI in rat would be translatable to humans due to the morphologic similarity of vascular injury between species regardless of mechanism. The histomorphologic
lexicon forDIVI in rat defines degenerative and adaptive findings of the vascular endotheliumand smoothmuscles, and characterizes inflammatory
components.We describe the mechanisms of these changes and their associationswith candidate biomarkers forwhich advanced analytical method validation
was completed. Further development is recommended for circulating microRNAs, endothelial microparticles, and imaging techniques. Recommendations
for sample collection and processing, analyticalmethods, and confirmation of target localization using immunohistochemistry and in situ hybridization
are described. The methods described are anticipated to aid in the identification and qualification of translational biomarkers for DIVI.

Item Type: Article
Keywords: animal mode,l arteritis, arteriopathy, non-clinical, vasculopathy, drug development tool, qualification
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45