Edoxaban (tosylate Monohydrate)

The Uses of Edoxaban (tosylate Monohydrate)

Edoxaban is an anticoagulant drug which acts as a direct factor Xa inhibitor.

Definition

ChEBI: A hydrate that is the monohydrate of the tosylate salt of edoxaban. Used for the treatment of deep vein thrombosis and pulmonary embolism.

Biological Activity

factor xa (fxa), a key serine protease, is a promising target enzyme for the prophylaxis and treatment of thromboembolic diseases. edoxaban tosylate monohydrate is a novel antithrombotic agent that directly inhibits fxa activity.

Clinical Use

Daichi Sankyo’s edoxaban tosilate is an orally administered coagulation factor Xa inhibitor that was approved and launched in Japan for the preventive treatment of venous thromboembolic events (VTE) in patients undergoing total knee arthroplasty, total hip arthroplasty, or hip fracture surgery. Edoxaban has been shown to have a rapid onset of anticoagulant effect due to short Tmax (1–2 h) after dosing and sustained for up to 24 h post-dose. Marketed under the brand name Lixiana, it is currently in phase III studies in the US for the prevention of stroke and systemic embolic events in patients with atrial fibrillation (AF) and venous thromboembolism (VTE).

in vitro

edoxaban tosylate monohydrate (du-176b) inhibited fxa with ki values of 0.561 nm for free fxa, 2.98 nm for prothrombinase, and exhibited >10 000-fold selectivity for fxa. du-176b doubled prothrombin time and activated partial thromboplastin time in human plasma. du-176b did not impair platelet aggregation by adp, collagen or u46619 [1].

in vivo

du-176b dose-dependently inhibited thrombus formation in rat and rabbit thrombosis models, although bleeding time in rats was not significantly prolonged at an antithrombotic dose [1].

Drug interactions

Potentially hazardous interactions with other drugs
Analgesics: increased risk of bleeding with NSAIDs and high dose aspirin; increased risk of haemorrhage with IV diclofenac and ketorolac - avoid
Anti-arrhythmics: concentration increased by dronedarone (reduce edoxaban dose)
Antibacterials: concentration increased by erythromycin (reduce edoxaban dose); concentration reduced by rifampicin.
Anticoagulants: increased risk of haemorrhage with other anticoagulants - avoid.
Antidepressants: concentration possibly reduced by St John’s wort.
Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone.
Antifungals: concentration increased by ketoconazole (reduce edoxaban dose).
Ciclosporin: concentration of edoxaban increased (reduce edoxaban dose).

Metabolism

Unchanged edoxaban is main form in plasma. Edoxaban is metabolised via hydrolysis (mediated by carboxylesterase 1), conjugation or oxidation by CYP3A4/5 (<10%). Edoxaban has 3 active metabolites, the predominant metabolite (M-4), formed by hydrolysis, is active and reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5%. Edoxaban is a substrate for the efflux transporter P-glycoprotein (P-gp), but not a substrate for uptake transporters such as organic anion transporter polypeptide OATP1B1, organic anion transporters OAT1 or OAT3 or organic cation transporter OCT2. Its active metabolite is a substrate for OATP1B1.
Renal clearance accounts for approximately 35% of the administered dose. Metabolism and biliary/intestinal excretion account for the remaining clearance.

References

[1] furugohri t, isobe k, honda y, kamisato-matsumoto c, sugiyama n, nagahara t, morishima y, shibano t. du-176b, a potent and orally active factor xa inhibitor: in vitro and in vivo pharmacological profiles. j thromb haemost. 2008;6(9):1542-9.
[2] bathala ms, masumoto h, oguma t, he l, lowrie c, mendell j. pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor xa inhibitor, in humans. drug metab dispos. 2012;40(12):2250-5.