Summary
We evaluated the relationship between antithrombotic effects and pharmacodynamic (PD)
marker changes produced by the novel factor (F)Xa inhibitors darexaban (YM150) and
rivaroxaban in a rabbit model of plaque disruption-induced arterial thrombosis. Animals
were subjected to catheter-induced endothelial denudation via the femoral artery followed
by a two-week high-cholesterol diet. Plaque disruption was induced by balloon angioplasty,
and then stasis was achieved by ligation at the distal side of the injured segment.
Darexaban and rivaroxaban were administered orally 1 hour (h) before and 9 h after
plaque disruption, and their antithrombotic effects were evaluated 24 h after the
initiation of ligation. Prothrombin time (PT), activated partial thromboplastin time
(APTT), and plasma FXa activity were measured using blood samples collected before
and 1 h after administration. Darexaban and rivaroxaban significantly reduced thrombus
formation. The thrombus weight obtained in the 30 mg/kg darexaban group was comparable
to that in the 1 mg/kg rivaroxaban group (2.17 ± 0.63 and 3.23 ± 1.64 mg, respectively,
vs. 8.01 ± 1.08 mg in the control group). Plasma FXa activity correlated with the
antithrombotic effects of darexaban and rivaroxaban, while PT only correlated with
those of darexaban. Our findings suggest that the degree of plasma FXa inhibition
may be useful for predicting antithrombotic effects of darexaban and rivaroxaban in
arterial thrombosis. PT may also be useful in evaluating antithrombotic effects of
darexaban in particular.
Keywords
Animal model - darexaban - FXa assay - rivaroxaban - thrombosis