Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies

Abstract

To cite this article: Wong PC, Crain EJ, Xin B, Wexler RR, Lam PYS, Pinto DJ, Luettgen JM, Knabb RM. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 2008; 6: 820-9.Summary. Background: Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. Objective: We evaluated the in vitro properties of apixaban and its in vivo activities in rabbit models of thrombosis and hemostasis. Methods: Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrically mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. Results: In vitro, apixaban is potent and selective, with a K i of 0.08 nM for human FXa. It exhibited species difference in FXa inhibition [FXa K i (nM): 0.16, rabbit; 1.3, rat; 1.7, dog] and anticoagulation [EC 2· (lM, concentration required to double the prothrombin time): 3.6, human; 2.3, rabbit; 7.9, rat; 6.7, dog]. Apixaban at 10 lM did not alter human and rabbit platelet aggregation to ADP, cthrombin, and collagen. In vivo, the values for antithrombotic ED 50 (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT and the values for BT ED 3· (dose that increased BT by 3-fold) were 0.27 ± 0.03, 0.11 ± 0.03, 0.07 ± 0.02 and > 3 mg kg warfarin, respectively. Conclusions: In summary, apixaban was effective in the prevention of experimental thrombosis at doses that preserve hemostasis in rabbits.

Apixaban Metabolism and Pharmacokinetics after Oral Administration to Humans

“…Apixaban has a high affinity for human factor Xa with a relatively low affinity for thrombin and trypsin; the high affinity and selectivity of apixaban may translate into improved pharmacologic characteristics versus those of the preceding oral factor Xa compounds, leading to an improved treatment option Wong et al, 2008). Positive results from a phase II clinical trial evaluating the prevention of venous thromboembolic events (asymptomatic and symptomatic deep vein thrombosis and nonfatal symptomatic pulmonary embolism) demonstrate the potential benefit of this agent versus standard therapy in anticoagulation monotherapy treatment (Lassen et al, 2007;Büller et al, 2008).…”

Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome

“…[4][5][6][7][8][9] Apixaban, an orally active, selective, direct factor Xa inhibitor, has been shown to reduce the incidence of venous thromboembolism in patients undergoing orthopedic surgery and to prevent thromboembolic events in patients with atrial fibrillation who are not candidates for oral vitamin K antagonist therapy. [10][11][12][13][14][15] We previously studied the use of apixaban, at doses of 5 to 20 mg daily, in patients who had had recent acute coronary syndromes and who were receiving aspirin or aspirin plus clopidogrel. 16 Treatment with apixaban resulted in dose-related increases in bleeding events and a trend toward fewer is chemic events.…”

Use of Thromboelastography (TEG) for Detection of New Oral Anticoagulants

“…Rivaroxaban and apixaban are oral direct inhibitors of factor Xa and are also competitive, selective, and not permanent. 11 Dabigatran is the only NOAC administered as a prodrug and metabolized to the active form. All 3 agents are licensed in the European Union and the United States to reduce the risk of venous thromboembolism in orthopedic surgical patients, as well as for stroke and systemic embolism in patients with nonvalvular atrial fibrillation.…”