Edoxaban: A Focused Review of its Clinical Pharmacology

Perspective:

This paper reviews important pharmacologic properties of edoxaban, the newest addition to the non-vitamin K oral antagonist (NOAC) agents. The following are six key points in the review:

1. Edoxaban is an oral, factor Xa inhibitor with predictable pharmacokinetic properties, similar to rivaroxaban and apixaban. These properties include a rapid onset of action (peak concentration observed at 1.5 hours), a short course of anticoagulant effect (~24 hours), no significant drug-food interactions, and few potential drug-drug interactions, leading to a predictable anticoagulant effect.

2. Similar to the other NOAC agents, there is no need for monitoring or dose adjustments in the vast majority of patients. Initial dose adjustment is necessary for patients with limited renal function (creatinine clearance 30-50 ml/min), low body weight (≤60 kg), or use of a potent P-glycoprotein inhibitor (e.g., verapamil or quinidine).

3. In two large phase III studies, edoxaban has been shown to be effective for stroke prevention in atrial fibrillation (e.g., in the ENGAGE AF-TIMI 48 trial) as well as for treatment and prevention of recurrent venous thromboembolism (e.g., Hokusai-VTE trial). Both studies have demonstrated the clinical effectiveness of edoxaban with lower rates of bleeding than standard therapy.

4. While the ENGAGE AF-TIMI 48 study compared both a high-dose strategy (60 mg of edoxaban once daily) and a low-dose strategy (30 mg of edoxaban once daily) versus warfarin, only the high-dose strategy of 60 mg daily (adjusted to 30 mg daily based on clinical characteristics noted above) is under review with both the Food and Drug Administration and the European Union regulatory agencies. This is the same dosing under review for treatment and prevention of recurrent venous thromboembolism.

5. In vivo concentration of edoxaban is well correlated with anti-Xa activity, suggesting a possible strategy for measuring its anticoagulant effect when clinically necessary. Various measures of anticoagulation (e.g., prothrombin time and activated partial thromboplastin time) were not affected by a fed or fasted state, ethnicity, or concurrent use of aspirin.

6. In vivo tests have demonstrated reversal of anticoagulation tests (e.g., prothrombin time) in patients treated with recombinant human factor VIIa, anti-inhibitor coagulation complex (FEIBA), and prothrombin complex concentrates after treatment with edoxaban. This allows for possible treatment strategies when patients treated with edoxaban present with significant bleeding events. Two other agents are under phase II investigation for the reversal of the NOAC agents, including edoxaban.

Clinical Topics: Anticoagulation Management, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Novel Agents, Statins

Keywords: Stroke, Quinidine, Morpholines, Thiophenes, Warfarin, Body Weight, Thiazoles, Venous Thromboembolism, Pyrazoles, Pyridines, Blood Coagulation Factors, United States Food and Drug Administration, European Union, Verapamil, Pyridones


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