Biomedical Engineering Reference
In-Depth Information
6.6 DEVELOPING A BIOMARKER-BASED ASSAY FOR
DRUG-INDUCED VASCULAR DAMAGE
A robust blood-based preclinical toxicity assay requiring only phlebotomy for sample
collection that predicts or corresponds to histopathological findings of vascular injury
is highly desirable. In 2005, the Expert Working Group on Drug-Induced Vascular
Injury, composed of toxicologists and pathologists from the pharmaceutical industry,
academia, and the Food and Drug Administration (FDA), stated that “aside from
histological methods, the detection, noninvasively, of acute drug-induced vascular
injury in animals or humans is not possible due to the lack of specific and sensitive
biomarkers of endothelial and/or vascular smooth muscle injury” [11] and this
remains the case as of this writing. Historically, vascular injury was monitored by
looking for changes in blood pressure (BP) and/or heart rate (HR) as vascular damage
was not observed without concomitant changes in these parameters. It was discovered
that some newer drug classes could cause vascular injury in animals without
measurable changes in BP or HR. Some examples are endothelin-receptor antago-
nists, dopamine (DA1) agonists, adenosine agonists, and later generation phospho-
diesterase 4 inhibitors. This problem is compounded by the relatively low therapeutic
index for some of these drugs. There is also a trend toward increasing frequency of
histological vascular lesions in preclinical toxicity studies and increasing pressure
from regulatory agencies (FDA and others) to identify reliable biomarkers. Given this,
a largemultiyear effort consisting of many individual studies andmultiple species was
undertaken with the task of developing a specific, sensitive, noninvasive method for
detection of drug-induced vascular injury that predicts or correlates with histopathol-
ogy in multiple animal species used in preclinical toxicity studies with a potential for
adaptation to a clinical setting.
6.6.1 Endothelial Model
A large portion of this effort was given to enumeration of circulating endothelial cells
(CECs) and/or circulating endothelial progenitors (CEPs) from rat blood (control
and tool compound treated), sorting of cell populations of interest, and subsequent
gene expression analysis (i.e., genechip, PCR, etc.). A rat model was chosen since it is
commonly used in preclinical drug development toxicity testing. Familiarity within
the department with existing drugs that induce mesenteric vasculopathy in rats was
also useful in providing tool compounds for method development and proof-of-
concept experiments.
CECs were first described decades ago as a possible indicator of drug-induced
vascular damage [12, 13], but few publications correlating CECs and drug-induced
injury exist. However, there have since been numerous publications describing
correlations between CEC numbers and various human disease states, and CEC
enumeration is gaining acceptance as a clinical biomarker of vascular disease [14].
Unfortunately, there is no consensus method for enumeration or immunophenotypic
definition of human CEC/CEP [15]. In addition, very few publications exist on
flow cytometry and CEC/CEP in animals. Lack of consensus methods made the
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