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Edoxaban: a summary


Edoxaban provides rapid and specific inhibition of Factor Xa, which is closely related to plasma concentrations; given the limitations with long-term warfarin therapy, once-daily edoxaban may provide a convenient long-term alternative for patients


Barbara Clark Lead Clinical Pharmacist, London Bridge Hospital, London, UK


The use of parenteral heparins and oral vitamin K antagonists (VKAs) for the prevention and treatment of venous and arterial thromboembolic disease presents limitations from both the clinical and the patient’s point of view. Non-vitamin K antagonist oral anticoagulants (NOACs) have recently been introduced in the clinic and offer clear advantages in terms of safety and convenience of use and dosing. Edoxaban, a selective and potent inhibitor of activated Factor X (Xa), is currently approved in the USA, the EU and Japan for the oral treatment of symptomatic VTE, including DVT and PE, and the prevention of stroke and systemic thromboembolic events in patients with non-valvular atrial fibrillation (NVAF).1–4


extensively tested worldwide in distinct prophylactic and therapeutic settings, and is currently undergoing clinical evaluation in specific patient sub- populations.


Mode of action, pharmacokinetics/ pharmacodynamics Unlike traditional VKAs, edoxaban targets directly a key protease – Factor Xa – in the coagulation cascade, responsible for the synthesis of thrombin from prothrombin. The agent shows an approximate 10,000-fold selectivity for factor Xa over thrombin and a competitive dose-dependent inhibition kinetic pattern. Early phase studies of edoxaban in adults showed consistency and predictability in pharmacokinetic parameters. The agent has a rapid onset of action and reaches maximum plasma


renal disease, and additional edoxaban dose adjustments may not be needed in this patient group.7


The agent has been


concentrations within 1–2 hours of dosing. Its inhibitory activity is sustained up to 24 hours, the half-life ranges from 10 to 14 hours, and plasma protein binding is lower than that observed for other NOACs, namely apixaban and rivaroxaban. Absolute oral bioavailability is 62%. Approximately 30% of the dose excreted is metabolised; the main routes of excretion are via faeces and urine, with primarily renal elimination.5


Unlike


warfarin, food intake does not affect the pharmacokinetic profile of edoxaban. Ethnicity and gender also do not significantly alter the absorption, elimination and inhibitory activity of edoxaban.6,7


Pharmacokinetics has been studied in patients with renal impairment. Lowering the dose of edoxaban in patients with severe renal impairment gave a similar safety profile and plasma levels to normal doses in patients with normal or mildly impaired renal function. Furthermore, haemodialysis had minimal effects on the clearance of edoxaban in patients with end-stage


Drug–drug interactions The most relevant drug–drug interactions occur with with strong P-glycoprotein (P-gp) inhibitors such as dronedarone, ketoconazole, erythromycin and cyclosporin, which require a dose reduction of edoxaban to 30mg. Co- administration of anti-arrhythmics such as amiodarone, by contrast, results in an increase in edoxaban exposure of much lower magnitude and therefore does not require dose adjustment of the NOAC. Aspirin at low doses and non-steroidal anti-inflammatory agents can be safely administered to patients receiving edoxaban.6,7


Exposure to edoxaban may


also increase in patients with a body weight of ≤60kg and moderate renal impairment.7


Edoxaban can be taken


with or without food, as studies have shown that the absorption, mean plasma concentration and a wide range of other PK characteristics are not affected.7 Administration of edoxaban substantially increases coagulation parameters such as the international normalised ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT) in a dose-dependent manner ex vivo. In healthy individuals, edoxaban plasma concentrations correlated with PT and aPTT. In Phase I and II trials conducted in healthy volunteers, edoxaban showed a favourable tolerability profile. Adverse events were of mild severity and no dose-dependent increase in treatment- emergent adverse events was observed.6,7


Side effects The most common side effects are www.hospitalpharmacyeurope.com 27


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