Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

Abstract

Coactivation of platelets and the blood coagulation cascade contributes to the pathophysiology of arterial thrombosis. Combination therapy with antiplatelet and anticoagulant drugs may be needed for maximizing the prevention and treatment of arterial thrombosis. Few studies have thoroughly investigated the combined antithrombotic and bleeding effects of these antithrombotic agents. We, therefore, evaluated the antithrombotic and bleeding profiles of dual and triple therapy with razaxaban, a direct factor Xa inhibitor, plus aspirin and/or clopidogrel in rabbit models of electrolytic injury-induced carotid artery thrombosis and cuticle bleeding time, respectively. Compounds were infused either IV or into the portal vein from 1 h before arterial injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. We first evaluated the antithrombotic potency of razaxaban, and examined its ex vivo effects on coagulation parameters to confirm its selectivity. Antithrombotic ED(50) of razaxaban averaged 0.22 +/- 0.05 mg/kg/h (n = 6). Razaxaban at 3 mg/kg/h IV produced full antithrombotic efficacy, increased significantly ex vivo activated partial thromboplastin time and prothrombin time by 2.2 +/- 0.1- and 2.3 +/- 0.1-fold, respectively, and inhibited ex vivo factor Xa activity significantly by 91 +/- 5% (n = 6, P < 0.05) without affecting ex vivo thrombin activity. Razaxaban at concentrations up to 10 muM did not alter in vitro platelet aggregation responses to ADP, gamma-thrombin or collagen. To identify additive or synergistic antithrombotic effects of the various combination therapies, we purposefully used marginally effective doses of razaxaban at 0.1 mg/kg/h, aspirin at 0.3 mg/kg/h and clopidogrel at 1 mg/kg/h. Dual combination of threshold doses of razaxaban and aspirin or clopidogrel produced an enhanced antithrombotic effect without further increases in bleeding time. When compared with dual therapy with aspirin and clopidogrel (38 +/- 5% increase in blood flow), addition of razaxaban increased blood flow to 75 +/- 5% without additional bleeding time effects (n = 6/group, P < 0.05). In summary, razaxaban was an effective antithrombotic agent in a rabbit model of arterial thrombosis. Low-dose razaxaban was useful in combination with sub-optimal doses of aspirin and/or clopidogrel for the prevention of occlusive arterial thrombosis without excessive bleeding.

Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits

“…in this study as these doses represented the antithrombotic ED 20 , ED 50 , and ED 80 doses of apixaban in monotherapy (i.e. doses that produced 20%, 50% and 80% reduction of thrombus weight in this thrombosis model, respectively, as determined in a separate study).…”

“…Antithrombotic ED 20 , ED 50 , and ED 80 doses were then determined using the four-parameter logistic equation,…”

“…Results: Control thrombus weight and BT averaged 8.6 ± 0.9 mg and 181 ± 12 s, respectively (n = 6 per group). Effective doses of apixaban that reduced thrombus weight by 20 and 50% (ED 20 and ED 50 ) were 0.04 and 0.3 mg kg )1 h )1 i.v., respectively. Addition of aspirin to…”

Reductive Isoxazole Ring Opening of the Anticoagulant Razaxaban Is the Major Metabolic Clearance Pathway in Rats and Dogs

“…Razaxaban showed potent antithrombotic efficacy in animal models and in patients with deep vein thrombosis (Wong et al, 2007). The chemical structure of razaxaban contains an isoxazole ring (Fig.…”

Design, Synthesis and Discovery of 1-(2-(6-Chloro-3-methylsulfonyl)-naphthyl)-1H-pyrazole-5-carboxylamides as Highly Potent Factor Xa Inhibitors

“…Clinical findings have confirmed the potential of fXa inhibition for producing excellent antithrombotic efficacy with minimal bleeding risk when compared to direct thrombin inhibitors. [2][3][4][5][6] Our previous communications have reported a series of 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as potent and selective fXa inhibitors with good oral bioavailability and half-life. [7][8][9] This class of fXa inhibitors, as represented by compounds 1-4, possesses a substituent either at the 6-position (chloro) or at the 3-position (methylsulfonyl, aminosulfonyl, aminocarbonyl, fluoro or cyano) on the P1 naphthalene moiety.…”