The Direct Factor Xa Inhibitor Apixaban Produces Broad Antithrombotic Activity with Limited Effects on Bleeding Time in Rats.

Apixaban is an oral, direct and highly selective factor Xa inhibitor which is in late stage clinical development for the prevention and treatment of thromboembolic diseases. Apixaban is potent against human and rat factor Xa (Ki = 0.08 and 1.3 nM, respectively). The efficacy/safety profile of apixaban was determined in experimental models of thrombosis and hemostasis performed in anesthetized rats. Thrombosis was induced either by topical application of FeCl₂ to the vena cava (VT) or carotid artery (AT), tissue factor infusion into the vena cava (TF-VT), or within an extracorporeal arterial-venous shunt (ST). Bleeding time was measured in response to template incision of the renal cortex. Apixaban was administered as a continuous i.v. infusion of 0.1, 0.3, 1 or 3 mg/kg/h starting 60 min before each experimental procedure (n=5 or 6 per dose). These respective doses increased the ex vivo prothrombin time by 1.3, 1.9, 3.0 and 3.9 times control baseline, and achieved plasma concentrations of 0.3, 1.4, 5.0 and 12.2 μM. In comparison to vehicle treatment, the 3 mg/kg/h dose of apixaban decreased thrombus weight by 90 ± 2% in VT, 62 ± 7% in TF-VT, 62 ± 4% in AT, and 79 ± 3% in ST (all p<0.05). A 50% thrombus weight reduction sufficient to prevent vascular occlusion in each model would require projected doses (mg/kg/h) of 0.4 (VT), 1.9 (TF-VT), 0.8 (AT) and 1.1 (ST). The lowest dose level which preserved carotid blood flow at the pre-injury level during thrombus formation was 0.3 mg/kg/h. Apixaban prolonged bleeding time in a dose-dependent manner with no effect detected at 0.1 and 0.3 mg/kg/h, while significant (p<0.05) increases of 1.34 ± 0.12 and 2.13 ± 0.17 times control were observed at 1 and 3 mg/kg/h, respectively. In comparison, aspirin increased bleeding time by 1.42 ± 0.1 times control (n=7, p<0.05) when tested at a 10 mg/kg dose, a dose which produced maximum cyclooxygenase inhibition. These studies predict a wide therapeutic index for apixaban based on the prevention of occlusive thrombosis in a variety of experimental models without excessive bleeding time prolongation. These results are consistent with the safety and efficacy observed with apixaban in phase II clinical trials.