Naproxen Has No Relevant Effect on the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BAY 59-7939 - An Oral, Direct Factor Xa Inhibitor.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1873-1873 ◽  
Author(s):  
Dagmar Kubitza ◽  
Michael Becka ◽  
Wolfgang Mueck ◽  
Michael Zuehlsdorf
Keyword(s):  
Clinical Trials ◽  
Venous Thromboembolism ◽  
Plasma Concentration ◽  
Adverse Events ◽  
Orthopaedic Surgery ◽  
Bleeding Time ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Major Orthopaedic Surgery

Abstract BAY 59-7939 is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. BAY 59-7939 compared favourably with enoxaparin in recent clinical trials of the prevention of venous thromboembolism following major orthopaedic surgery. Possible concomitant medications in patients receiving BAY 59-7939 for either the prevention or treatment of venous thromboembolism include non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen. This randomized, two-way crossover study was performed to investigate the influence of naproxen on the safety, tolerability, pharmacodynamics, and pharmacokinetics of BAY 59-7939 in 11 healthy male subjects. The study included a run-in period with naproxen. Treatments were: naproxen 500 mg on 2 consecutive days (run-in), followed by a 14-day washout period, and then randomization either to BAY 59-7939 15 mg; or to naproxen 500 mg on the first day, and naproxen 500 mg and BAY 59-7939 15 mg on the second day. There was a 14-day washout period between crossovers. BAY 59-7939, naproxen, and the combination were well tolerated. Adverse events (eight in total) were reported by three subjects, and all were mild in intensity; there were no drug-related, treatment-emergent adverse events. BAY 59-7939 significantly inhibited Factor Xa activity by 35%, and prolonged prothrombin time (by 1.4 times baseline [tb]), activated partial thromboplastin time (1.3 tb), and HepTest (1.9 tb), with no influence from naproxen. No interaction was observed with respect to collagen-stimulated platelet aggregation. BAY 59-7939 and naproxen together significantly increased bleeding time compared with BAY 59-7939 alone; however, this difference was small compared with naproxen alone for all but one subject. This indicates that some subjects may be more sensitive to the combined effect of naproxen and BAY 59-7939. However, analysis of patients’ data from clinical trials after major orthopaedic surgery showed similar bleeding risks in patients with and without co-medication with NSAIDs at BAY 59-7939 doses up to 10 mg twice daily. The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) for BAY 59-7939 both increased by approximately 10% following co-administration of naproxen; however, this small increase in BAY 59-7939 bioavailability was not considered clinically relevant. In conclusion, there is no relevant interaction between BAY 59-7939 and naproxen, although some individuals may be more sensitive to a combination of these drugs. Initial analysis of data from phase II clinical trials of BAY 59-7939 has shown a similar bleeding risk in patients using NSAIDs concomitantly compared with BAY 59-7939 alone. This will be further substantiated in phase III trials. Parameter Naproxen BAY 59-7939 BAY 59-7939 + naproxen aGeometric mean/geometric coefficient of variation; bMedian relative change from baseline; N=11 for all data Bleeding time (tb)a 1.46/0.583 1.20/0.613 2.17/0.576 Platelet aggregationb 0.052 1.02 0.086 AUC (μg.h/L)a - 1250/28.56 1396/26.30 Cmax (μ g/L)a - 152.9/31.51 165.3/27.69

scholarly journals Edoxaban for Venous Thromboembolism Treatment—The New Kid on The Block for Latin America. A Practical Guide

2018 ◽  
Vol 24 (9_suppl) ◽  
pp. 340S-349S ◽  
Author(s):  
Eduardo Ramacciotti ◽  
Valéria Cristina Resende Aguiar ◽  
Valter Castelli Júnior ◽  
Ivan Benaducce Casella ◽  
Antonio Eduardo Zerati ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Latin America ◽  
Venous Thromboembolism ◽  
Oral Anticoagulant ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Clinical Use ◽  
Direct Oral Anticoagulant ◽  
Direct Factor ◽  
Practical Guide

Edoxaban, a direct factor Xa inhibitor (FXa), is the fourth direct oral anticoagulant (DOAC) approved for clinical use in the treatment of venous thromboembolism (VTE) in Latin America, following global approvals for this indication. Edoxaban features some particular characteristics when compared to the previously approved DOACs. This review summarizes the main properties of edoxaban, the outcomes results of its pivotal global clinical trials and the peculiar clinical features of this compound. This practical guide aims to help Latin America clinicians understand edoxaban, its proper indication and its use for the appropriate patients with VTE.

Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, and acetylsalicylic acid

2006 ◽  
Vol 95 (02) ◽  
pp. 224-228 ◽  
Author(s):  
Markus Hinder ◽  
Annke Frick ◽  
Ronald Rosenburg ◽  
Galina Hesse ◽  
Marie-Laure Ozoux ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Acetylsalicylic Acid ◽  
Platelet Function ◽  
Bleeding Time ◽  
Factor Xa ◽  
Pharmacokinetic Parameters ◽  
Parameter Estimates ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Geometric Means

SummaryThe pharmacokinetics, pharmacodynamics and safety of the direct factor Xa inhibitor, otamixaban, with and without concomitant acetylsalicylic acid (ASA) were investigated in healthy volunteers. The study was a double-blind, placebo-controlled 3-way crossover study. Sixty-eight male volunteers in total were randomised to otamixaban, ASA, or otamixaban with ASA. ASA (300 mg once a day) was started2 days before and continued on the day of the otamixaban 6-hour IV infusion (0.3 and 0.5 mg/kg). Pharmacokinetic and pharmacodynamic parameters (coagulation markers, platelet function tests and skin bleeding time) were determined. Drug interaction was assessed by the ratios of geometric means and 90 confidence intervals (90% CI)of the parameter estimates.Pharmacokinetic parameters of otamixaban remain ed unchanged with ASA. Ratios of geometric means (90% CI) were for Ceoi 96.54 (91.21–102.19) and 95. 04 (90. 10–100. 24) and for AUC 98. 0 (93. 92–102. 25) and 95. 90 (92. 61–99. 31), for 0. 3 and 0. 5 mg/kg, respectively. No drug interaction was observed between otamixaban andASA on the coagulation and platelet function parameters. Neither otamixaban nor ASA had an effect on skin bleeding time; their co-administration led toa slight prolongation of skin bleeding time above the normal range without any clinically relevant bleeding. This study demonstrated that the desired effects of otamixaban and ASA, namely anticoagulation and platelet inhibition, respectively, are maintained during co-administration of both drugs.

scholarly journals Comparison of the effects of edoxaban, an oral direct factor Xa inhibitor, on venous thromboembolism between patients with and without cancer

2018 ◽  
Vol 72 (2) ◽  
pp. 120-127 ◽  
Author(s):  
Satoshi Ikeda ◽  
Seiji Koga ◽  
Yuki Yamagata ◽  
Masamichi Eguchi ◽  
Daisuke Sato ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Direct Factor

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.

YM150, An Oral Direct Factor Xa Inhibitor: Combination with Aspirin or Clopidogrel In Arteriovenous Shunt Thrombosis In Rats

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3318-3318
Author(s):  
Yoshiyuki Iwatsuki ◽  
Chinatsu Sakata ◽  
Yumiko Moritani
Keyword(s):  
Platelet Aggregation ◽  
Arterial Thrombosis ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Control Level ◽  
Factor Xa ◽  
Antiplatelet Agents ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Silk Thread

Abstract Abstract 3318 Background: YM150, an oral direct factor Xa inhibitor, is currently in clinical development for the prevention of venous thromboembolism in patients undergoing orthopedic surgery, prevention of stroke in patients with atrial fibrillation, and prevention of ischemic events after recent acute coronary syndrome (ACS). The antiplatelet agents aspirin or clopidogrel will likely be co-prescribed with YM150 in ACS. Here, we report the effects of YM150 in combination with aspirin or clopidogrel on thrombus formation, bleeding, platelet aggregation, and coagulation in rats. Methods: The antithrombotic effect was estimated in a rat arteriovenous shunt model. The shunt was formed by attaching a polyethylene tube containing a silk thread to the carotid artery and the contralateral carotid vein. Blood was allowed to circulate in this shunt for 15 min, and then the silk thread was withdrawn from the tube to assess the thrombus weight. YM150, aspirin, or clopidogrel was orally administered 0.5, 1, or 2 h before shunt formation, respectively. At the same time as shunt formation, an incision was made at the sole of the left foot using a template bleeding device (Surgicutt®) to measure bleeding time. To avoid interference with the thrombosis model, blood samples to assess platelet aggregation and prothrombin time were obtained from separate animals at the same time point as shunt formation in the thrombus study. Platelet aggregation was induced using 10 μg/mL of collagen and 5 μM of adenosine 5`-diphosphate (ADP) to assess the effects of aspirin and clopidogrel, respectively. Results: YM150 alone inhibited thrombus formation, with significance at 10 mg/kg and more (P < 0.05). Respective thrombus weights in the control, 3, 10, and 30 mg/kg groups of YM150 were 4.8, 3.6, 2.4, and 2.0 mg. Aspirin alone inhibited thrombus formation, with significance at 100 mg/kg and more (P < 0.01). Respective thrombus weights in the control, 30, 100, and 300 mg/kg group of aspirin were 6.2, 4.2, 2.8, and 1.5 mg. Clopidogrel alone inhibited thrombus formation, with significance at 1 mg/kg and more (P < 0.01). Respective thrombus weights in the control, 0.3, 1, and 3 mg/kg group of clopidogrel were 4.8, 3.6, 2.9, and 1.3 mg. When administered concomitantly with 100 mg/kg of aspirin, YM150 (3, 10, 30 mg/kg) further inhibited thrombogenesis, with significance at 30 mg/kg of YM150 (P < 0.05) and thrombus weights of 2.4, 1.5, and 1.3 mg, respectively. When administered concomitantly with 1 mg/kg of clopidogrel, YM150 (3, 10, 30 mg/kg) further inhibited thrombogenesis, with significance at 30 mg/kg of YM150 (P < 0.05) and thrombus weights of 3.0, 2.0, and 1.5 mg, respectively. Collagen-induced platelet aggregation was reduced to 16.7% of the control level by 100 mg/kg of aspirin, and ADP-induced platelet aggregation was reduced to 74.4% of the control level by 1 mg/kg of clopidogrel. These effects were not changed in the presence of YM150. Prothrombin time and bleeding time were not prolonged by any of the agents alone, and further, these parameters were not affected by combined use of YM150 with either aspirin or clopidogrel. Conclusions: The thrombosis study suggests that both the platelet aggregation and coagulation cascade participate in thrombus formation in this model since both antiplatelet agents and the anticoagulant YM150 were effective. Thus, the thrombosis induced in this model can be considered similar to arterial thrombosis in humans where both platelets and fibrin are involved. Taken together, YM150 is a promising antithrombotic agent that augments the effects of antiplatelet agents against arterial thrombosis without increasing bleeding risk. Disclosures: Iwatsuki: Astellas Phama Inc.: Employment. Sakata:Astellas Phama Inc.: Employment. Moritani:Astellas Phama Inc.: Employment.

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