DU‐176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles

Abstract

Summary. Background: Factor Xa (FXa), a key serine protease that converts prothrombin to thrombin in the coagulation cascade, is a promising target enzyme for the prophylaxis and treatment of thromboembolic diseases. DU-176b is a novel antithrombotic agent that directly inhibits FXa activity. Objective: To evaluate the in vitro pharmacological profiles and in vivo effects of DU-176b in animal models of thrombosis and bleeding. Methods: In vitro, FXa inhibition, specificity and anticoagulant activities were examined. Oral absorption was studied in rats and cynomolgus monkeys. In vivo effects were studied in rat and rabbit models of venous thrombosis and tail bleeding. Results: DU-176b inhibited FXa with Ki values of 0.561 nM for free FXa, 2.98 nM for prothrombinase, and exhibited >10 000-fold selectivity for FXa. In human plasma, DU-176b doubled prothrombin time and activated partial thromboplastin time at concentrations of 0.256 and 0.508 lM, respectively. DU-176b did not impair platelet aggregation by ADP, collagen or U46619. DU-176b was highly absorbed in rats and monkeys, as demonstrated by more potent anti-Xa activity and higher drug concentration in plasma following oral administration than a prototype FXa inhibitor, DX-9065a. In vivo, DU-176b dose-dependently inhibited thrombus formation in rat and rabbit thrombosis models, although bleeding time in rats was not significantly prolonged at an antithrombotic dose. Conclusions: DU-176b is a more potent and selective FXa inhibitor with high oral bioavailability compared with its prototype, DX-9065a. DU-176b represents a promising new anticoagulant for the prophylaxis and treatment of thromboembolic diseases.

The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism

“…In rat and rabbit thrombosis models, edoxaban dose-dependently inhibited thrombus formation and bleeding time in rats was not significantly prolonged at an antithrombotic dose. A subsequent in vitro study confirmed the concentration-dependent and competitive inhibition of human Factor Xa by edoxaban, without affecting platelet aggregation (Furugohri et al, 2008).…”

Factor Xa Inhibitors

“…3.4) is a potent, highly selective factor Xa inhibitor with a high affinity for free factor Xa (K i 0.56 nM) and for factor Xa bound to the prothrombinase complex (K i 2.98 nM) [40]. It has predictable and consistent pharmacokinetics with dose proportional increases in plasma concentrations, and a half-life of approximately 10-14 h [10,41,42].…”

Use of novel oral anticoagulant agents in venous thromboembolism

“…This medication should be started 5-10 days after initiation of a parenteral anticoagulant. Similar to rivaroxaban, edoxaban is a selective inhibitor of factor Xa (33,34). The peak plasma concentration is achieved in 1 to 2 hours and steady state is achieved in , major bleeding was defined as: RE-COVER, RE-COVER II, EINSTEIN DVT, EINSTEIN PE, AMPLIFY, HOKUSAI VTE, if it was clinically overt and if it was associated with a fall in the hemoglobin level of at least 20 g per liter, resulted in the need for transfusion of 2 or more units of red cells, involved a critical site, or was fatal; ∑ , clinically relevant non-major bleeding was defined as: RE-COVER, RE-COVER II, AMPLIFY, HOKUSAI VTE, at least one of the following: spontaneous skin hematoma of at least 25 cm 2 , spontaneous nosebleed more than 5 minutes duration, macroscopic hematuria, spontaneous rectal bleeding, gingival bleeding for more than 5 minutes, bleeding leading to hospitalization and/or surgical treatment, bleeding leading to a transfusion of less than 2 units of whole blood or red cells, any other bleeding considered clinically relevant by the investigator; EINSTEIN DVT, EINSTEIN PE, overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of study treatment, or associated with any other discomfort such as pain or impairment of activities of daily life.…”