Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 597939) – an oral, direct factor Xa inhibitor

2007 ◽  
Vol 97 (03) ◽  
pp. 471-477 ◽  
Author(s):  
Elisabeth Perzborn ◽  
Philip Friederich ◽  
Marcel Levi ◽  
Ulf Buetehorn ◽  
Harry Büller ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Factor Xa ◽  
Vehicle Control ◽  
Venous Stasis ◽  
Treatment Model ◽  
Direct Factor ◽  
Experimental Thrombosis ◽  
Prevention And Treatment ◽  
Prevention Model ◽  
Fxa Inhibitor

SummaryCurrent anticoagulant therapies for the prevention and treatment of thromboembolic disorders have many drawbacks: vitamin K antagonists interact with food and drugs and require frequent laboratory monitoring, and heparins require parenteral administration. Oral rivaroxaban (BAY 597939) is a new, highly selective and potent direct factor-Xa (FXa) inhibitor with a predictable pharmacodynamic and pharmacokinetic profile and could therefore be an attractive antithrombotic drug. It was the objective of this study to investigate the antithrombotic efficacy of oral rivaroxaban in two rabbit models of experimental venous thrombosis. In the venous stasis (prevention) model, animals were randomized to receive oral rivaroxaban 0.3, 1.0, 3.0 or 10.0 mg/kg or vehicle control. Thrombosis was induced by jugular vein stasis and injection of thromboplastin into the ear vein. In the venous thrombosis (treatment) model, intravenous (1.0 and 3.0 mg/kg) and oral (3.0 mg/kg) rivaroxaban was compared with intravenous nadroparin (40 U bolus and 20 U/h), fon-daparinux (42 Mg/kg) and vehicle control. Thrombus growth was assessed by measuring the accretion of radiolabeled fibrinogen into preformed clots in the jugular veins. Bleeding was assessed using an ear bleeding model. In the prevention model, rivaroxaban reduced thrombus formation dose-dependently (calculated ED50 1.3 mg/kg). In the treatment model, oral rivaroxaban (3.0 mg/kg) reduced thrombus growth to a similar extent to intravenous rivaroxaban (1.0 mg/kg), nadroparin and fondapari-nux. Oral rivaroxaban did not prolong bleeding time. In conclusion, the orally available selective, direct FXa inhibitor rivaroxaban is effective in the prevention and treatment of venous thrombosis in two well-established models of experimental thrombosis.

The Oral, Direct Factor Xa Inhibitor BAY 59-7939 Does Not Cross-React with Anti-Heparin/PF4 (Heparin-Induced Thrombocytopenia) Antibodies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1883-1883 ◽  
Author(s):  
Jeanine M. Walenga ◽  
Debra Hoppensteadt ◽  
Omer Iqbal ◽  
Brian Neville ◽  
Walter P. Jeske ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Positive Response ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Standards Of Care ◽  
Direct Thrombin Inhibitors ◽  
Direct Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Prevention And Treatment ◽  
Fxa Inhibitor

Abstract BAY 59-7939 is an orally bioavailable, small-molecule, direct Factor Xa (FXa) inhibitor in advanced clinical trials for the prevention and treatment of thromboembolic disorders. Unfractionated heparin and the low molecular weight heparins (LMWHs) are the current standards of care for patients requiring anticoagulation. However, their use can be restricted by heparin-induced thrombocytopenia (HIT), which may be associated with severe thrombotic complications. It has been reported previously that fondaparinux, a heparin-derived pentasaccharide that indirectly inhibits FXa, does not cross-react with anti-heparin/PF4 (HIT) antibodies. However, we have shown that increased sulfation of fondaparinux does result in strong cross-reactivity with HIT antibodies, leading to platelet activation/aggregation. Previous studies have shown that direct thrombin inhibitors (DTIs), such as argatroban and lepirudin, do not cross-react with HIT antibodies. Current guidelines for patients who have HIT recommend use of a DTI to prevent or treat associated thrombosis. This study was performed to evaluate whether BAY 59-7939 cross-reacts with HIT antibodies, in order to examine its potential as an alternative anticoagulant for the management of patients with HIT. The effect of BAY 59-7939 on platelet activation mediated by HIT antibodies was examined in sera collected from 63 patients diagnosed with HIT (HIT sera), using platelet aggregation assays, the [14C]serotonin release assay, and flow cytometry for the detection of platelet P-selectin expression and platelet microparticle formation. Heparin, the LMWH enoxaparin, fondaparinux, and the DTI melagatran were included for comparison. BAY 59-7939 did not activate platelets or cause aggregation with any of the HIT sera tested, establishing that there is no interaction between BAY 59-7939 and HIT antibodies. As expected, heparin strongly activated platelets and caused their aggregation, and gave a positive response with 100% of the HIT sera tested. Enoxaparin showed positive responses with 73% of the sera. Of all the HIT sera tested, one exhibited a weak positive response with fondaparinux. As has been observed with other DTIs, melagatran did not cause any platelet activation or aggregation responses with the HIT sera. This study clearly demonstrates that BAY 59-7939, a novel, orally active, direct FXa inhibitor, does not interact with preformed HIT antibodies. Therefore, BAY 59-7939 has potential as a new option for the prevention and treatment of thrombosis in patients with HIT.

Comparative Antithrombotic and Antihemostatic Effects of the Direct Factor Xa Inhibitors, Apixaban and Rivaroxaban, and the Direct Thrombin Inhibitors, Dabigatran and Lepirudin, in Rabbit Models of Venous Thrombosis and Bleeding Time

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3025-3025
Author(s):  
Pancras C. Wong ◽  
Earl Crain ◽  
Carol Watson
Keyword(s):  
Venous Thrombosis ◽  
Bleeding Time ◽  
Vena Cava ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Coronary Syndrome ◽  
Prevention And Treatment ◽  
Fxa Inhibitor ◽  
Stable Plasma

Abstract Background: Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development for the prevention and treatment of venous thromboembolism, stroke prevention in patients with atrial fibrillation, and secondary prevention in patients with acute coronary syndrome. The objective of this study was to assess the antithrombotic and antihemostatic effects of apixaban in rabbits, compared to the direct FXa inhibitor, rivaroxaban, and thrombin inhibitors, dabigatran and lepirudin. Methods: We induced the formation of non-occlusive thrombus in venous thrombosis (VT) models by placing threads in the vena cava, and induced bleeding by the incision of cuticles in anesthetized rabbits. Apixaban, rivaroxaban, dabigatran and lepirudin were given as a bolus injection and supplemented with a constant IV infusion to achieve a stable plasma level. Results: Control thrombus weight in the prevention VT model ranged from 65±3 to 88±5 mg, and in the VT treatment model ranged from 76±5 to 90±5 mg. Control bleeding time (BT) ranged from 163±5 s to 173±8 s (n=6 per group). In the prevention VT model, apixaban, rivaroxaban, dabigatran and lepirudin (infusion started at 30 min before VT initiation) exhibited dose-related efficacy in preventing VT with ED50s (doses for 50% reduction of control thrombus weight; mg/kg) of 0.17±0.003, 0.15±0.03, 0.37±0.04 and 0.24±0.07 mg/kg, respectively. Apixaban, rivaroxaban and dabigatran, at doses for 80% reduction of control thrombus weight, prolonged BT by 13±2, 91±9*, 343±38* and 505±12%*, respectively (*P<0.05, vs. apixaban, n=6 per group). In the treatment VT model, these inhibitors (infusion started at 30 min after VT initiation) were equally effective in preventing growth of a preformed thrombus. Clot regression was observed following administration of apixaban, rivaroxaban and dabigatran at 2.7 mg/kg, and lepirudin at 3.5 mg/kg. The preformed thrombus decreased from an initial weight of 38±2 mg to 26±4*, 17±2*, 20±3* and 25±1* mg, respectively (*P<0.05, vs. control, n=6 per group). Conclusion: In summary, apixaban was as efficacious as rivaroxaban, dabigatran and lepirudin in the prevention and treatment VT models in rabbits. At equivalent antithrombotic doses, apixaban preserved hemostasis better than the other three agents in the rabbit cuticle BT model. Clinical studies will be required to assess the therapeutic windows in humans.

Dose-Dependent Antithrombotic Effects of Apixaban, an Oral Direct Factor Xa Inhibitor, in Prevention and Treatment of Thrombosis in Rabbit Models of Arteriovenous-Shunt and Venous Thrombosis at Doses That Preserve Hemostasis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 933-933 ◽  
Author(s):  
Pancras C. Wong ◽  
Earl J. Crain ◽  
Donald J. Pinto ◽  
Carol A. Watson
Keyword(s):  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Factor Xa ◽  
Arteriovenous Shunt ◽  
Thrombin Inhibitor ◽  
Phase Ii Trials ◽  
Prevention And Treatment ◽  
Fxa Inhibitor ◽  
Dose Dependent

Abstract Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor, which is currently in late stage clinical development for the prevention and treatment of thromboembolic diseases. The dose-dependent antithrombotic and antihemostatic profile of apixaban was determined in the rabbit models of arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), and cuticle bleeding time (BT), and compared to those of the direct thrombin inhibitor lepirudin, the indirect FXa inhibitor fondaparinux and the oral anticoagulant warfarin. We induced the formation of thrombus in the AVST and VT models by placing threads in the extracorporeal shunt and vena cava, respectively, and bleeding by the incision of cuticles in anesthetized rabbits. In the AVST and VT prevention models, apixaban (0.03 to 3 mg/kg/h), lepirudin (0.006 to 0.75 mg/kg/h) and fondaparinux (0.01 to 1 mg/kg/h) were infused IV 30–60 min before the initiation of thrombosis. Warfarin (0.1 to 3 mg/kg/day) was administered orally for 4 days before the study. Control thrombus weight averaged 290±11 mg and 64±2 mg in AVST and VT, respectively, and control BT averaged 179±5 s (n=6 per group). Apixaban exhibited similar dose-related efficacy as lepirudin, fondaparinux, and warfarin in preventing AVST and VT. At doses that prevented 80 to 90% of thrombus formation in AVST and VT, apixaban, fondaparinux, lepirudin and warfarin increased BT by 20±2, 30±5, 500±10, 502±20%, respectively (n=6 per group). Doses for 50% reduction of control thrombus weight in AVST, VT were 0.27±0.03, 0.11±0.02 mg/kg/h IV for apixaban, 0.04±0.01, 0.05±0.01 mg/kg/h IV for lepirudin, 0.05±0.01, 0.05±0.005 mg/kg/h IV for fondaparinux and 0.53±0.04, 0.27±0.02 mg/kg PO for warfarin, respectively. To increase BT by 3-fold required higher doses of apixaban and fondaparinux (>3 mg/kg/h IV), lepirudin (0.24±0.05 mg/kg/h IV) and warfarin (0.70±0.07 mg/kg PO). In a VT treatment model, apixaban, lepirudin and fondaparinux, administered IV as a bolus injection supplemented with a continuous infusion after thrombus formation, were all able to arrest thrombus growth. However clot regression was only observed following administration of apixaban (0.6 mg/kg+0.87 mg/kg/h IV) where the preformed thrombus decreased from an initial weight of 38±2 mg (n=6) to 26±4 mg (n=6; P<0.05). In summary, apixaban and fondaparinux were effective in the prevention and treatment of experimental thrombosis at doses that preserve hemostasis in rabbits. Warfarin and lepirudin also prevented thrombus formation but with greater increases in BT. Furthermore, these standard anticoagulant agents have well-known limitations including narrow therapeutic index, frequent laboratory monitoring, or the requirement of parenteral administration. The favorable preclinical antithrombotic and antihemostatic profile of apixaban demonstrated here is consistent with clinical efficacy and safety results in recent Phase II trials, and indicates that direct inhibition of FXa with apixaban is a promising approach for the prevention and treatment of venous thromboembolism.

scholarly journals Management of direct factor Xa inhibitor–related major bleeding with prothrombin complex concentrate: a meta-analysis

2019 ◽  
Vol 3 (2) ◽  
pp. 158-167 ◽  
Author(s):  
Siavash Piran ◽  
Rasha Khatib ◽  
Sam Schulman ◽  
Ammar Majeed ◽  
Anne Holbrook ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Prothrombin Complex Concentrate ◽  
Meta Analysis ◽  
Case Series ◽  
Factor Xa ◽  
The United States ◽  
Effective Management ◽  
Direct Factor ◽  
All Cause Mortality ◽  
Fxa Inhibitor

Abstract A targeted antidote for reversal of direct factor Xa (FXa) inhibitors is now available for clinical use in the United States, but it is costly and has limited availability. In a systematic review, we evaluated the safety and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) as an alternative for managing direct FXa inhibitor–related major bleeding. A systematic literature search was conducted using Medline, Embase, and the Cochrane Register of Controlled Trials up to September 2018. No comparative studies were found. Ten case series with 340 patients who received PCC for direct FXa inhibitor–related major bleeding were included. The pooled proportion of patients with effective management of major bleeding was 0.69 (95% confidence interval [CI], 0.61-0.76) in 2 studies using the International Society on Thrombosis and Haemostasis (ISTH) criteria and 0.77 (95% CI, 0.63-0.92) in 8 studies that did not use the ISTH criteria; all-cause mortality was 0.16 (95% CI, 0.07-0.26), and thromboembolism rate was 0.04 (95% CI, 0.01-0.08). On the basis of evidence with very low certainty from single-arm case series, it is difficult to determine whether 4F-PCC in addition to cessation of direct oral FXa inhibitor is more effective than cessation of direct oral FXa inhibitor alone in patients with direct FXa inhibitor–related major bleeding.

Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents

2012 ◽  
Vol 107 (02) ◽  
pp. 253-259 ◽  
Author(s):  
Toshio Fukuda ◽  
Yuko Honda ◽  
Chikako Kamisato ◽  
Toshiro Shibano ◽  
Yoshiyuki Morishima
Keyword(s):  
Venous Thrombosis ◽  
Prothrombin Complex Concentrate ◽  
Bleeding Time ◽  
Factor Viia ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Thrombosis Model ◽  
Haemostatic Agents

SummaryEdoxaban, an oral, direct factor Xa inhibitor, has a similar or low incidence of bleeding events compared with other anticoagulants in clinical trials. Therefore, agents to reverse the anticoagulant effects of edoxaban could be desirable in emergency situations. In this study, the reversal effects of haemostatic agents were determined on prothrombin time (PT) prolongation in vitro and bleeding time prolongation in vivo by edoxaban. PT using human plasma was measured in the presence of edoxaban at therapeutic and excess concentrations with the haemostatic agents, prothrombin complex concentrate (PPSB-HT), activated prothrombin complex concentrate (Feiba), and recombinant factor VIIa (rFVIIa). In rats, rFVIIa and Feiba was given during intensive anticoagulation with edoxaban. The haemostatic effect was evaluated in a model of planta template bleeding and a potential prothrombotic effect was evaluated in a venous thrombosis model. PPSB-HT, Feiba, and rFVIIa concentration-dependently shortened PT prolonged by edoxaban. Among these, rFVIIa and Feiba showed potent activities in reversing the PT prolongation by edoxaban. rFVIIa (1 and 3 mg/kg, i.v.) and Feiba (100 U/kg, i.v.) significantly reversed edoxaban (1 mg/kg/h)-induced prolongation of bleeding time in rats. In a rat venous thrombosis model, no potentiation of thrombus formation was observed when the highest dose (3 mg/kg) of rFVIIa was added to edoxaban (0.3 and 1 mg/kg/h) compared with the control. The present study indicated that rFVIIa, Feiba, and PPSB-HT have the potential to be reversal agents for edoxaban.

Animal Models of Thrombosis Help Predict the Human Therapeutic Concentration of PRT54021, a Potent Oral Factor Xa Inhibitor.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 901-901 ◽  
Author(s):  
Keith Abe ◽  
Gail Siu ◽  
Susan Edwards ◽  
Pei Hua Lin ◽  
Bing Yan Zhu ◽  
...  
Keyword(s):  
Animal Models ◽  
Venous Thrombosis ◽  
Thrombin Generation ◽  
Ex Vivo ◽  
Vena Cava ◽  
Factor Xa ◽  
Fold Change ◽  
In Vivo Models ◽  
Antithrombotic Activity ◽  
Fxa Inhibitor

Abstract Factor Xa (fXa) inhibition has resulted in the emergence of a new class of antithrombotics. Pharmacodynamic monitoring of these agents has proven problematic. The present study was designed to determine the target concentration of an oral fXa inhibitor required for clinical trials using both thrombin generation assays and three in vivo models and determine whether clotting assays such as activated partial thromboplastin time (aPTT) and prothrombin time (PT) would be suitable for monitoring human dosing. PRT54021 (PRT021) is a potent inhibitor of human fXa (Ki=117pM). PRT021 and fondaparinux, an indirect fXa inhibitor, both significantly inhibited TAT and F1.2 generation in human whole blood. Compared to a therapeutic level of fondaparinux (200nM), PRT021 (200nM) was more potent in suppressing both markers. Multiple doses of PRT021 were evaluated in three animal models. The first model, which measured clot accretion on cotton threads placed in rabbit abdominal vena cava, compared inhibition of thrombus mass by PRT021 to that of supratherapeutic doses of enoxaparin (a LMW heparin). The second model compared the ability of PRT021 to maintain vessel patency under arterial flow conditions in FeCl3 induced thrombosis in rat carotid artery to that achieved by enoxaparin or clopidogrel (an antiplatelet agent). The third model investigated inhibition of 111In labeled platelet deposition on dacron grafts and expansion chambers placed in femoral arteriovenous shunts in baboons. PRT021 and enoxaparin were administered as IV infusions and clopidogrel was dosed orally for three days. Ex vivo PT and aPTT were measured in all models. The models encompass stringent criteria of arterial and venous thrombosis and PRT021 produced dose-responsive antithrombotic activity in each of the three models. The efficacy of PRT021 compared favorably to supratherapeutic levels of enoxaparin and clopidogrel. Unlike in the rodent models, efficacy in primates was attained at a much lower dose with minimal prolongation of PT. Species specificity was also demonstrated by in vitro extensions of PT and aPTT in rat, rabbit, baboon and human plasma. A 2X change of PT was attained at concentrations of 8.9, 1.6, 1 and 0.4μM respectively. The data indicate that doses of PRT021 that inhibit thrombin generation in human blood and that provide anticoagulation similar to baboon dosed at 0.49mg/kg may be sufficient to prevent venous thrombosis in humans. Comparative modeling of extents of change in PT to levels of antithrombotic efficacy also leads us to predict that human therapeutic activity for PRT021 may be attained without concurrent changes in ex vivo clotting parameters. The targeted concentration is currently being tested in Phase II trials for its ability to prevent venous thromboembolism in orthopedic surgery patients. Model of Thrombosis Agent, Dose Antithrombotic Activity aPTT fold change PT fold change Rabbit vena cava PRT021,3mg/kg 76% inhibition 2.22 2.34 Rabbit vena cava Enoxaparin, 1.6mg/kg 96% inhibition 2.06 2.01 Rat carotid PRT021,19.1mg/kg 90% patency 1.69 2.20 Rat carotid Enoxaparin, 7.6mg/kg 70% patency 3.49 1.19 Rat carotid Clopidogrel, 3mg/kg/day 80% patency 1.03 1.01 Baboon arteriovenous PRT021,0.49mg/kg 90% inhibition (venous), 32% inhibition (arterial) 1.29 1.17

Rivaroxaban Has Protective Effects in a Model of Disseminated Intravascular Coagulation (DIC) in Rats.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 935-935 ◽  
Author(s):  
Elisabeth Perzborn ◽  
Claudia Hirth-Dietrich ◽  
Elke Fischer ◽  
Martin Groth ◽  
Elke Hartmann ◽  
...  
Keyword(s):  
Platelet Count ◽  
Disseminated Intravascular Coagulation ◽  
Interleukin 6 ◽  
Factor Xa ◽  
Selective Inhibition ◽  
Vehicle Control ◽  
Protective Effects ◽  
Intravascular Coagulation ◽  
Serious Infection ◽  
Fxa Inhibitor

Abstract Introduction: DIC is a complication that occurs during serious infection with Gram-negative bacteria. Endotoxin is a component of the bacterial cell wall that elicits a cytokine-mediated cascade of tissue factor-dependent hypercoagulable reactions. The resulting hypercoagulable state may be inhibited by potent anticoagulation. Rivaroxaban is an oral, direct Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. The aim of this study was to examine the effects of rivaroxaban in a rat model of endotoxin-induced DIC. Methods: Rivaroxaban (0.1–10 mg/kg p.o.) or vehicle control (PEG400/H2O 60/40%, 5 mL/kg p.o.) were administered 30 minutes before endotoxin injection (lipopolysaccharide O55 B5 [LPS], 250 μg/kg i.v.) to conscious rats. Blood samples were withdrawn from anesthetized animals by heart puncture 4 hours after LPS injection and fibrinogen, platelet count, thrombin-antithrombin (TAT) complex levels and IL-6 were measured. Results: The induction of DIC was indicated in the placebo + LPS group vs vehicle control by decreased fibrinogen (2.12±0.08 vs 2.69±0.10 g/L) and platelet count (571±28 vs 904±30×109/L) an increase in TAT (75±9 vs 2±1 μg/L) and IL-6 (8.6±1.23 μg/L vs 0.028±0.020 μg/L). Pretreatment with rivaroxaban (0.1–10 mg/kg p.o.) dose-dependently ameliorated the effects of LPS on fibrinogen, platelets and TAT. Rivaroxaban 10 mg/kg p.o. normalized fibrinogen (2.58±0.07 g/L) and TAT (5.6±1.2 μg/L) and increased platelet count (703±19×109/L) (Table). Rivaroxaban also slightly reduced the plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) (4.24±0.67 μg/L). Conclusions: These results show that direct, selective inhibition of FXa by rivaroxaban effectively normalized the hypercoagulable reactions of endotoxemia with a slight modulating effect on the generation of pro-inflammatory active cytokines, such as IL-6, in the rat DIC model. Further research into the use of rivaroxaban in the management of DIC is therefore warranted. Effects of rivaroxaban in an endotoxin-induced DIC model in rats 4 hours after LPS injection. Results show mean ± SEM. Vehicle control Placebo + LPS Rivaroxaban 1 mg/kg + LPS Rivaroxaban 10 mg/kg + LPS DIC, disseminated intravascular coagulation; IL-6, interleukin-6; LPS, lipopolysaccharide O55 B5; SEM, standard error of the mean; TAT, thrombin-antithrombin ## p<0.01 vs sham, ### p<0.001 vs sham, *p<0.05 vs LPS/placebo, ** p<0.01 vs LPS/placebo, *** p<0.001 vs LPS/placebo Fibrinogen (g/L) 2.69±0.10 n=5 2.12±0.08## n=14 2.41±0.09 n=14 2.58± 0.07** n=7 Platelets (×109/l) 904±30 n=5 571±28### n=8 655±23 n=6 703±19* n=7 TAT (μg/L) 1.8±0.8 n=5 75.2±9.4### n=14 65.3±8.0 n=14 5.6±1.2*** n=7 IL-6 (μg/ml) 0.028±0.020 n=5 8.60±1.23### n=6 5.01±0.47 n=6 4.24±0.67 n=7

In Vitro Characteristics, Anticoagulant Effects and In Vivo Antithrombotic Efficacy of a Novel, Potent and Orally Active Direct Factor Xa Inhibitor, DU-176b.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1862-1862 ◽  
Author(s):  
Yoshiyuki Morishima ◽  
Taketoshi Furugohri ◽  
Koji Isobe ◽  
Yuko Honda ◽  
Chikako Matsumoto ◽  
...  
Keyword(s):  
Oral Administration ◽  
Factor Xa ◽  
Coagulation Cascade ◽  
Venous Stasis ◽  
Factor Xa Inhibitor ◽  
Fxa Inhibitor ◽  
Antithrombotic Efficacy ◽  
Orally Active

Abstract Factor Xa (FXa) is a key serine protease in the coagulation cascade and is a promising target enzyme for developing a new antithrombotic agent. Our first clinical candidate for a small molecular direct FXa inhibitor DX-9065a potently inhibits FXa (Ki = 41 nM) and exerts antithrombotic effects in animal models. However, due to its poor bioavailability (10% in monkeys) the compound is used only as an injectable formulation in clinical studies. Here we report in vitro characteristics of serine proteases inhibition, anticoagulant effects and in vivo antithrombotic efficacy of DU-176b, a novel, potent and orally active direct FXa inhibitor. DU-176b competitively inhibited human FXa with a Ki value of 0.561 nM, indicating 70-fold increase in FXa inhibitory activity compared with DX-9065a. DU-176b demonstrated 10,000-fold selectivity relative to inhibition of thrombin (Ki = 6.00 μM), and had no effects on the enzymatic activities of factor VIIa, t-PA, plasmin, trypsin and chymotrypsin. In human plasma, DU-176b prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) in a concentration-dependent manner. Its concentrations for doubling these clotting times were 0.256 and 0.508 μM, respectively. After oral administration of DU-176b to rats, significant anti-Xa activity was observed in plasma over 4 h. The oral bioavailability of DU-176b (approximately 50%) was significantly higher than that of DX-9065a (10%) in monkeys. The antithrombotic efficacy of DU-176b was examined by oral administration to rats 30 minutes prior to thrombogenic stimuli. In a venous stasis thrombosis model, DU-176b (0.5 – 12.5 mg/kg, p.o.) dose-dependently inhibited thrombus formation, prolonged PT, and revealed plasma anti-Xa activity. DU-176b also exerted significant anticoagulant effect in a rat model of tissue factor-induced disseminated intravascular coagulation at doses of 0.1 – 2.5 mg/kg, p.o. These results demonstrate that DU-176b is a potent and selective factor Xa inhibitor that possesses antithrombotic effect after oral administration. DU-176b has the potential to be clinically useful for prophylaxis and treatment of several thrombotic diseases.

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