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Briefing Therapeutic Approaches in Anticoagulant, Thrombolytic, and Antiplatelet Therapy
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Edoxaban was approved in July 2011 in Japan for the prevention of venous thromboembolisms (VTE) following lower-limb orthopedic surgery. It was also approved by the FDA in January 2015 for the prevention of stroke and non-central nervous system systemic embolism. It inhibits free factor Xa and prothrombinase activity and inhibits thrombin-induced platelet aggregation [50]. Portola submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval to market betrixaban for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients with risk factors for VTE [51]. Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma. The development of darexaban was discontinued in September 2011 [52]. Otamixaban is an experimental injectable anticoagulant direct factor Xa inhibitor that was investigated for the treatment for acute coronary syndrome. In 2013, Sanofi announced that the drug candidate showed poor performance in a Phase III clinical trial [53]. The advantages of the xabans over vitamin K antagonists include no requirement for routine anticoagulation monitoring as well as a fast and reliable onset of action [54–56].
Investigational drugs for the treatment of acute myocardial infarction: focus on antiplatelet and anticoagulant agents
Published in Expert Opinion on Investigational Drugs, 2019
Srikanth Yandrapalli, Gabriela Andries, Shashvat Gupta, Abdel Rahman Dajani, Wilbert S. Aronow
Darexaban (YM150) is an oral direct inhibitor of factor Xa. It has a rapid onset of action, reaches maximum plasma levels at 1–1.5 h post-dose, and has a terminal half-life of 14–18 h [97]. The safety and tolerability of this drug were evaluated in a phase 2 clinical trial, the RUBY-1, which was a randomized, double-blind, placebo-controlled trial of the safety and tolerability of darexaban following ACS [98]. Patients with ACS were randomized to either placebo or one out of six dosing group for darexaban (5 mg BID, 10 mg once daily, 15 mg BID, 30 mg once daily, 30 mg BID, and 60 mg daily) on top of appropriate antiplatelet therapy as per guidelines. Similar to prior oral anticoagulant trials, darexaban group had increased risk of major and clinically relevant non-major bleeding events compared to placebo in a dose-dependent manner. Unfortunately, the increased in bleeding risk was not accompanied by any significant benefit in the efficacy end-point (composite of death, stroke, AMI, systemic thromboembolism, and severe recurrent ischemia) [98], halting the investigation of darexaban treatment in AMI patients.
Combination oral antithrombotic therapy for the treatment of myocardial infarction: recent developments
Published in Expert Opinion on Pharmacotherapy, 2018
Udaya S. Tantry, Eliano P. Navarese, Aung Myat, Rahul Chaudhary, Paul A. Gurbel
In a Phase II study, darexaban compared to placebo was associated with a dose-dependent increase in the rates of ISTH major and clinically relevant non-major bleeding without any reduction in composite ischemic end points (death, MI, stroke, systemic thromboembolism, and severe recurrent ischemia) [57]. Darexaban has not been further studied for ACS patients.