Nonclinical Safety Biomarkers of Drug-induced Vascular Injury

Abstract

Better biomarkers are needed to identify, characterize, and/or monitor drug-induced vascular injury (DIVI) in nonclinical species and patients. The Predictive Safety Testing Consortium (PSTC), a precompetitive collaboration of pharmaceutical companies and the U.S. Food and Drug Administration (FDA), formed the Vascular Injury Working Group (VIWG) to develop and qualify translatable biomarkers of DIVI. The VIWG focused its research on acute DIVI because early detection for clinical and nonclinical safety monitoring is desirable. The VIWG 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 for DIVI in rat defines degenerative and adaptive findings of the vascular endothelium and smooth muscles, and characterizes inflammatory components. We describe the mechanisms of these changes and their associations with candidate biomarkers for which advanced analytical method validation was completed. Further development is recommended for circulating microRNAs, endothelial microparticles, and imaging techniques. Recommendations for sample collection and processing, analytical methods, 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.

Biomarkers of translational medicine

“…В настоящее время в качестве перспективных рассматриваются такие маркеры, как VEGF, GRO/CINC-1, TIMP-1, vWGpp, NGAL, TSP-1, α-актин гладкой мус кулатуры, кальпонин и трансгелин [21,25]. Ввиду морфологической схожести сосудистых поражений у человека и крысы предполагается, что маркеры ПИПС, применяемые на этапе доклинических испытаний, могут быть использованы в исследованиях на человеке [27].…”

Temporal Patterns of Novel Circulating Biomarkers in IL-2-mediated Vascular Injury in the Rat

“…Novel candidate DIVI biomarkers (angiopoietin-2, E-selectin, chemokine [C-X-C motif] ligand-1, lipocalin-2, monocyte chemotactic protein-1, tissue inhibitor of metalloproteinase-1, vascular endothelial growth factor A, a-1-acid glycoprotein [orosomucoid], endothelin-1, total nitrite, and thrombospondin-1) were measured using previously described methods (Mikaelian et al 2014). The novel candidate biomarker data of 1 rat in the recovery group were excluded from the analysis because they did not fall in the range for the measured analytes, thereby suggesting sample degradation.…”

“…Despite different inciting causes and outcomes, vasculitides share multiple common features, including activation and damage to endothelial cells (ECs) and inflammation. Thus, the Vascular Injury Working Group (VIWG) of the Predictive Safety Testing Consortium of the Critical Path Institute (PSTC) is assessing candidate biomarkers of DIVI in research animals (Mikaelian et al 2014), while the ''Safer and Faster Evidence-based Translation'' program of the innovative medicine initiative is doing the same in humans (Bendjama et al 2014;Bendjama et al 2013).…”

Cardiovascular safety risk assessment for new candidate drugs from functional and pathological data: Conference report

“…Although vascular lesions are not frequently encountered in safety assessment studies (Mikaelian et al, 2014), their interpretation and relevance to man are confounded by factors including spontaneous vascular pathology and species differences. In-life monitoring is difficult as many biomarkers used for the detection of vascular injury are nonspecific or time-dependent.…”