Intravenous and oral antithrombotic efficacy of the novel platelet GPIIb/IIIa antagonist roxifiban (DMP754) and its free acid form, XV459

Currently used antiplatelet drugs, including aspirin, ticlopidine, and othe rs, are effective against certain but not all of the many endogenous platel et activators. Because of their limited efficacy, a significant number of s erious thromboembolic complications still occur, highlighting the need for a more effective therapy. DMP754 (roxifiban), a prodrug of XV459, is a rece ntly discovered, potent antiplatelet agent with high affinity and specifici ty for platelet GPIIb/IIIa receptors that blocks platelet aggregate formati on regardless of the agonist (IC50=0.030 to 0.05 mu mol/L) or anticoagulant used for blood collection. DMP754 rapidly converts to its active free-acid form, XV459, which has a comparable high affinity for both resting and act ivated platelets (K-d=1 to 2 nmol/L) and a relatively slow rate of dissocia tion from resting platelets. The present study was undertaken to determine intravenous and oral antithrombotic efficacies of DMP754 and XV459 and to c ompare them with those of other antiplatelet and anticoagulant agents in ca nine models of arterial thrombosis. In these models, thrombosis was induced either electrolytically (200-mu A anodal current) in the carotid artery or mechanically by external clamping of the femoral artery along with stenosi s, which resulted in either total occlusive thrombus formation or cyclic fl ow reduction, respectively. DMP754 and XV459 were given either intravenousl y (0.1 mg/kg bolus) or orally (0.1 to 0.4 mg/kg). Additionally, the antithr ombotic efficacies of DMP754, aspirin, heparin, and ticlopidine in the cani ne carotid artery electrolytic injury model were compared. DMP754 demonstra ted oral bioavailability of 20.8% in dogs after administration at different doses and prevented cyclic flow reduction (ED90-100= <0.1 mg/kg IV or PO). Additionally, both DMP754 and XV459 (0.1 mg/kg IV or 0.3 to 0.4 mg/kg PO) demonstrated maximal antithrombotic efficacy in preventing electrically ind uced carotid and coronary artery thrombosis and significant antithrombotic efficacy (P<0.001) at relatively low doses in different settings of arteria l thrombosis in the canine model. DMP754 resulted in a significant reductio n in thrombus mass and sustained arterial blood flow with 100% prevention o f occlusive and nonocclusive thrombosis. In contrast, administration of asp irin (10 mg/kg PO for 2 days), heparin (10 IU/kg IV bolus followed by 90 IU /kg TV infusion over 3 hours), or ticlopidine (300 mg/kg PO for 3 days) bef ore initiation of arterial thrombosis did not reduce the incidence of elect rolytic injury-induced occlusive arterial thrombosis. These studies demonst rated a distinct antithrombotic efficacy of DMP754 as compared with existin g strategies and suggest potential intravenous and oral antithrombotic uses of DMP754 in the prevention and treatment of thromboembolic disorders.