Pharmacokinetics and Pharmacodynamics of Edoxaban, a Non-Vitamin K Antagonist Oral Anticoagulant that Inhibits Clotting Factor Xa

Abstract

Edoxaban, a once daily non-vitamin K antagonist oral anticoagulant, is a direct, selective, reversible inhibitor of factor Xa (FXa). In healthy subjects, single oral doses of edoxaban result in peak plasma concentrations within 1.0–2.0 h of administration, followed by a biphasic decline. Exposure is approximately dose proportional for once daily doses of 15–150 mg. Edoxaban is predominantly absorbed from the upper gastrointestinal tract, and oral bioavailability is approximately 62 %. Food does not affect total exposure to edoxaban. The terminal elimination half-life in healthy subjects ranges from 10 to 14 h, with minimal accumulation upon repeat once daily dosing up to doses of 120 mg. The steady-state volume of distribution is approximately 107 L, and total clearance is approximately 22 L/h; renal clearance accounts for approximately 50 % of total clearance, while metabolism and biliary secretion account for the remaining 50 %. Intrinsic factors, such as age, sex and race, do not affect edoxaban pharmacokinetics after renal function is taken into account. Oral administration of edoxaban results in rapid changes in anticoagulatory biomarkers, with peak effects on anticoagulation markers (such as anti-FXa), the prothrombin time and the activated partial thromboplastin time occurring within 1–2 h of dosing.

Efficacy and Safety of Edoxaban in Patients With Active Malignancy and Atrial Fibrillation: Analysis of the ENGAGE AF‐TIMI 48 Trial

“…All DOACs may interact with certain chemotherapeutic agents through the P‐glycoprotein transporter;15 however, unlike rivaroxaban and apixaban, edoxaban has little inhibitory effect on CYP3A4 20. This may be particularly relevant in patients undergoing chemotherapy because CYP3A4 is responsible for metabolism of several anticancer therapies, including tyrosine kinase inhibitors 39.…”

“…Edoxaban, an oral direct factor Xa inhibitor with a short half‐life (10–14 hours) and minimal interaction with the cytochrome P‐450 system,20 was evaluated in the ENGAGE AF‐TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48) trial 21. Both higher‐dose (HDER) and lower‐dose (LDER) edoxaban regimens were noninferior to well‐managed warfarin in preventing stroke or systemic embolic events (SEEs) in patients with AF, and both regimens reduced bleeding and cardiovascular death 22.…”

New oral anticoagulants for Atrial Fibrillation

“…[38][39][40] In healthy subjects, single oral doses of edoxaban result in peak plasma concentrations within 1.0-2.0 hour of administration, followed by a biphasic decline. Exposure is approximately dose proportional for once daily doses of 15-150 mg.…”

“…38 Oral administration of edoxaban results in rapid changes in anticoagulatory biomarkers, with peak effects on anticoagulation markers (such as anti-FXa), PT and aPTT occurring within 1-2 h of dosing. 40 Although no specific antidote for edoxaban is currently available, hemostatic agents reverse its anticoagulant effect.…”

Pharmacological profile of non-vitamin K antagonist oral anticoagulants

“…The bioavailability is 62%. Its volume of distribution is 170 L and its half-life ranges from 10 to 14 h (EMA, 2016;FDA, 2016;Ogata et al, 2010;Lip and Agnelli, 2014;Parasrampuria and Truitt, 2016). The absorption, elimination, peak concentration and half-life of a single 60-mg dose of edoxaban are not affected by food (Ogata et al, 2010).…”