title: Intravenous and oral antithrombotic efficacy of the novel platelet GPIIb/IIIa antagonist roxifiban (DMP754) and its free acid form, XV459.
abstract: Currently used antiplatelet drugs, including aspirin, ticlopidine, and others, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. DMP754 (roxifiban), a prodrug of XV459, is a recently discovered, potent antiplatelet agent with high affinity and specificity for platelet GPIIb/IIIa receptors that blocks platelet aggregate formation regardless of the agonist (IC(50)=0.030 to 0.05 micromol/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 activated platelets (K(d)=1 to 2 nmol/L) and a relatively slow rate of dissociation from resting platelets. The present study was undertaken to determine intravenous and oral antithrombotic efficacies of DMP754 and XV459 and to compare them with those of other antiplatelet and anticoagulant agents in canine models of arterial thrombosis. In these models, thrombosis was induced either electrolytically (200-microA anodal current) in the carotid artery or mechanically by external clamping of the femoral artery along with stenosis, which resulted in either total occlusive thrombus formation or cyclic flow reduction, respectively. DMP754 and XV459 were given either intravenously (0.1 mg/kg bolus) or orally (0.1 to 0.4 mg/kg). Additionally, the antithrombotic efficacies of DMP754, aspirin, heparin, and ticlopidine in the canine carotid artery electrolytic injury model were compared. DMP754 demonstrated oral bioavailability of 20.8% in dogs after administration at different doses and prevented cyclic flow reduction (ED(90-100)=<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 induced carotid and coronary artery thrombosis and significant antithrombotic efficacy (P<0.001) at relatively low doses in different settings of arterial thrombosis in the canine model. DMP754 resulted in a significant reduction in thrombus mass and sustained arterial blood flow with 100% prevention of occlusive and nonocclusive thrombosis. In contrast, administration of aspirin (10 mg/kg PO for 2 days), heparin (10 IU/kg IV bolus followed by 90 IU/kg IV infusion over 3 hours), or ticlopidine (300 mg/kg PO for 3 days) before initiation of arterial thrombosis did not reduce the incidence of electrolytic injury-induced occlusive arterial thrombosis. These studies demonstrated a distinct antithrombotic efficacy of DMP754 as compared with existing strategies and suggest potential intravenous and oral antithrombotic uses of DMP754 in the prevention and treatment of thromboembolic disorders.
authors.affiliation: DuPont Pharmaceuticals Company, Wilmington, DE 19880-0400, USA. shaker.a.mousa@dupontpharma.com
authors.forename: S A
authors.initials: SA
authors.lastname: Mousa
authors.forename: R
authors.initials: R
authors.lastname: Kapil
authors.forename: D X
authors.initials: DX
authors.lastname: Mu
mesh_terms: D000284:Administration, Oral; D000578:Amidines / Q000097:blood / Q000493:pharmacokinetics*; D000596:Amino Acids / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001760:Bleeding Time; D004195:Disease Models, Animal; D004285:Dogs; D004597:Electroshock; D005260:Female; D005263:Femoral Artery / Q000293:injuries; D006801:Humans; D007275:Injections, Intravenous; D007555:Isoxazoles / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D010973:Platelet Adhesiveness / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy*
chemical_list: D000578:Amidines; D000596:Amino Acids; D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C104284:XV 459; C118235:roxifiban