Biomarkers and Mechanisms of Drug-Induced Vascular Injury in Non-Rodents

Abstract

In preclinical safety studies, drug-induced vascular injury can negatively impact candidate-drug selection because there are no obvious diagnostic markers for monitoring this pathology preclinically or clinically. Furthermore, our current understanding of the pathogenesis of this lesion is limited. While vasodilatation and increased shear stress appear to play a role, the exact mechanism(s) of injury to the primary target cells, smooth muscle (SMC) and endothelial cell (EC), are unknown. Evaluation of potential novel markers for clinical monitoring with a mechanistic underpinning would add value in risk assessment and risk management. This mini review focuses on the efforts and progress to identify diagnostic markers as well as understanding the mechanism of action in nonrodent drug-induced vascular injury.

Coronary and Systemic Arterial Physiology and Immunohistochemical Markers Related to Early Coronary Arterial Lesions in Beagle Dogs Given the Potassium Channel Opener, ZD6169, or the Endothelin Receptor Antagonist, ZD1611

“…demonstrated that animals given either 60 or 240 mg/kg ZD6169 showed increases in plasma vWF of more than 60% of prestudy values, as early as 1.5 hr post-dosing that remained at 6 hr and gradually declined below pre-study levels thereafter to 24 hr post dose. and Newsholme et al (2000) have suggested that vWF plasma levels fall quickly post-dosing due to several possible causes, and the conclusions of these latter publications and those of and Louden et al (2006) were that vWF plasma levels alter due to numerous stimuli, are rapidly transient, and thus render this molecule inappropriate for use as a specific biomarker of DIVI. However, we have demonstrated in our studies that its presence within plasma makes it a useful diagnostic indicator of plasma penetration into damaged arteries caused by ZD6169 and ZD1611.…”

Scientific and Regulatory Policy Committee Points-to-consider Paper*

“…Kerns et al 2005; C. Louden et al 2006;Newsholme et al 2000;Stagliano et al 2001;Thomas et al 2009;Thomas et al 2012;Turk 2010;Weaver et al 2008;Zhang et al, 2002b;Zhang et al 2006;2012). The majority of candidate biomarkers have included factors involved in EC activation , edema, inflammation, tissue remodeling, (Blake, and Ridker 2001;Dalmas et al 2008;Daguès, Pawlowski, Guigon, et al 2007;) and maintenance of vascular tone (C. Louden et al 2006). The search for DIVI markers has been formalized, with the formation of a collaborative consortium of industry, academic, and regulatory experts into The Predictive Safety Testing Consortium (PSTC) Vascular Injury Working Group (VIWG), and a panel of biomarkers for DIVI has been proposed (Mikaelian et al 2014).…”

“…These have included circulating proteins, and even genomic markers, but their utility has been limited by their potential qualification with only a very limited number of compounds, most of which are vasoactive molecules (Brott et al 2005;, Daguès, Pawlowski, Guigon, G, et al 2007Dalmas et al 2008Dalmas et al , 2011Enerson et al 2006;Joseph, Rees, and Dayan 1996;W. Kerns et al 2005; C. Louden et al 2006;Newsholme et al 2000;Stagliano et al 2001;Thomas et al 2009;Thomas et al 2012;Turk 2010;Weaver et al 2008;Zhang et al, 2002b;Zhang et al 2006;2012). The majority of candidate biomarkers have included factors involved in EC activation , edema, inflammation, tissue remodeling, (Blake, and Ridker 2001;Dalmas et al 2008;Daguès, Pawlowski, Guigon, et al 2007;) and maintenance of vascular tone (C. Louden et al 2006).…”

“…Although small molecule DIVI tends to involve specific vessels (especially small-to medium-sized arterioles) in particular vascular beds (W. Kerns et al 2005; C. Louden et al 2006), biotherapeutic-mediated DIVI lesion distribution is often more widespread and vascular lesions can occur in capillaries, venules, and occasionally larger arteries. Thickening of the vascular intima is often noted, with loss of endothelium accompanying EC activation, and disruption of the underlying elastic lamina.…”

“…The difference in pathophysiologic mechanisms between small molecule DIVI, which are often considered direct injuries to the vasculature, and those related to biotherapeutics, which are mainly immune-mediated indirect mechanisms, are discussed. Since there have been several recent reviews of potential biomarkers for DIVI (Bendjama et al 2014;C. Louden et al 2006;Mikaelian et al 2014;Zhang et al 2010), this article will only briefly summarize work in vascular biomarkers related to small molecule development and will instead focus on recent biomarkers not previously reviewed and those especially relevant to biotherapeutics.…”