Edoxaban

Synonyms :
Edoxaban Tosylate, Edoxaban Tosylate Monohydrate, N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide

Status : approved

Description

Edoxaban is a member of the Novel Oral Anti-Coagulants (NOACs) class of drugs, and is a rapidly acting, oral, selective factor Xa inhibitor. By inhibiting factor Xa, a key protein in the coagulation cascade, edoxaban prevents the stepwise amplification of protein factors needed to form blood clots. It is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF) and for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5-10 days of initial therapy with a parenteral anticoagulant. Traditionally, warfarin, a vitamin K antagonist, was used for stroke prevention in these individuals but effective use of this drug is limited by it’s delayed onset, narrow therapeutic window, need for regular monitoring and INR testing, and numerous drug-drug and drug-food interactions. This has prompted enthusiasm for newer agents such as dabigatran, apixaban, and rivaroxaban for effective clot prevention. In addition to once daily dosing, the benefits over warfarin also include significant reductions in hemorrhagic stroke and GI bleeding, and improved compliance, which is beneficial as many patients will be on lifelong therapy.

Used

Edoxaban is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). However, it should not be used in patients with creatinine clearance (CrCL) > 95 mL/min because of increased risk of ischemic stroke compared to warfarin at the highest dose studied (60 mg). It is also indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5-10 days of initial therapy with a parenteral anticoagulant.

Mechanism Of Action

Edoxaban is a selective inhibitor of factor Xa, a serine endopeptidase of the clotting cascade required for cleavage of prothrombin into thrombin.

Dosage

Form Route Strength
Tablet, film coated oral 15 mg
Tablet, film coated oral 30 mg
Tablet, film coated oral 60 mg

Pharmacodynamics

Administration of edoxaban results in prolongation of clotting time tests such as aPTT (activated partial thromboplastin time), PT (prothrombin time), and INR (international normalized ratio).

Toxic Effect

Premature discontinuation of any oral anticoagulant, including edoxaban, in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If edoxaban is discontinued for reasons other than pathological bleeding or completion of a course of therapy, consider the use of another anticoagulant. Edoxaban increases the risk of potentially fatal major bleeding such as intracranial hemorrhage and gastrointestinal bleeding. Patients should be educated on how to watch for signs of major and minor bleeding and when to seek medical help. Co-administration of other anti-coagulants, anti-platelets, or thrombolytics may increase the risk of bleeding and should therefore be avoided.

Metabolism

Edoxaban is not extensively metabolized by CYP3A4 resulting in minimal drug-drug interactions. However, it does interact with drugs that inhibit p-gp (p-glycoprotein), which is used to transport edoxaban across the intestinal wall. Unchanged edoxaban is the predominant form in plasma. There is minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation, and oxidation by CYP3A4. The predominant metabolite M-4, formed by hydrolysis, is human-specific and 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% of exposure to edoxaban.

Absorption

Following oral administration, peak plasma edoxaban concentrations are observed within 1-2 hours. Absolute bioavailability is 62%.

Half Life

The terminal elimination half-life of edoxaban following oral administration is 10 to 14 hours.

Protein Binding

In vitro plasma protein binding is ~55%.

Elimination Route

Edoxaban is eliminated primarily as unchanged drug in urine. Renal clearance (11 L/hour) accounts for approximately 50% of the total clearance of edoxaban (22 L/hour). Metabolism and biliary/intestinal excretion account for the remaining clearance.

Clearance

22 L/hr

Volume of Distribution

The steady state volume of distribution is 107 L.

Chemical Classification

Chemical Name

Edoxaban Tosylate

Brands

name Dosage form Country
Savaysa tablet, film coated US
Savaysa tablet, film coated US
Savaysa tablet, film coated US

Drug Drug Interactions

  •  Abciximab  : Edoxaban may enhance the anticoagulant effect of Anticoagulants.
  •  Abiraterone  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Acenocoumarol  : May enhance the anticoagulant effect of Anticoagulants.
  •  Acetylsalicylic acid  : May enhance the anticoagulant effect of Anticoagulants.
  •  Alteplase  : May enhance the anticoagulant effect of Anticoagulants.
  •  Amiodarone  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Anistreplase  : May enhance the anticoagulant effect of Anticoagulants.
  •  Apixaban  : May enhance the anticoagulant effect of Anticoagulants.
  •  Argatroban  : May enhance the anticoagulant effect of Anticoagulants.
  •  Atorvastatin  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Azithromycin  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Bivalirudin  : May enhance the anticoagulant effect of Anticoagulants.
  •  Carvedilol  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Citric Acid  : Edoxaban may enhance the anticoagulant effect of Anticoagulants.
  •  Clarithromycin  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Cobicistat  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Crizotinib  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Cyclosporine  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Dabigatran etexilate  : May enhance the anticoagulant effect of Anticoagulants.
  •  Daclatasvir  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Dalteparin  : May enhance the anticoagulant effect of Anticoagulants.
  •  Danaparoid  : May enhance the anticoagulant effect of Anticoagulants.
  •  Darunavir  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Dasatinib  : May enhance the anticoagulant effect of Anticoagulants.
  •  Deferasirox  : Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.
  •  Deoxycholic Acid  : Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased.
  •  Desogestrel  : May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects.
  •  Dicoumarol  : Edoxaban may enhance the anticoagulant effect of Anticoagulants.
  •  Dipyridamole  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Dronedarone  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Dydrogesterone  : May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects.
  •  Edetic Acid  : Edoxaban may enhance the anticoagulant effect of Anticoagulants.
  •  Eliglustat  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Enoxaparin  : May enhance the anticoagulant effect of Anticoagulants.
  •  Erythromycin  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Ethyl biscoumacetate  : Edoxaban may enhance the anticoagulant effect of Anticoagulants.
  •  Flibanserin  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Fondaparinux sodium  : May enhance the anticoagulant effect of Anticoagulants.
  •  Gestodene  : May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects.
  •  Heparin  : May enhance the anticoagulant effect of Anticoagulants.
  •  Ibritumomab  : Anticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to an increased risk of bleeding.
  •  Ibrutinib  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Itraconazole  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Ivacaftor  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Ketoconazole  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Lapatinib  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Ledipasvir  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Lomitapide  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Lopinavir  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Mefloquine  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Mirabegron  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Nadroparin  : May enhance the anticoagulant effect of Anticoagulants.
  •  Nicardipine  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Nilotinib  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Nintedanib  : Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased.
  •  Obinutuzumab  : Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased.
  •  Pentosan Polysulfate  : May enhance the anticoagulant effect of Anticoagulants.
  •  Phenindione  : Edoxaban may enhance the anticoagulant effect of Anticoagulants.
  •  Phenprocoumon  : Edoxaban may enhance the anticoagulant effect of Anticoagulants.
  •  Progesterone  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Propranolol  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Quinidine  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Quinine  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Ranolazine  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Reserpine  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Reteplase  : May enhance the anticoagulant effect of Anticoagulants.
  •  Ridogrel  : May enhance the anticoagulant effect of Anticoagulants.
  •  Rifampicin  : May decrease the serum concentration of Edoxaban.
  •  Ritonavir  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Rivaroxaban  : Anticoagulants may enhance the anticoagulant effect of Rivaroxaban.
  •  Salicylate-sodium  : May enhance the anticoagulant effect of Anticoagulants.
  •  Saquinavir  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Simeprevir  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Streptokinase  : May enhance the anticoagulant effect of Anticoagulants.
  •  Sugammadex  : May enhance the anticoagulant effect of Anticoagulants.
  •  Sulfisoxazole  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Sulodexide  : Edoxaban may enhance the anticoagulant effect of Anticoagulants.
  •  Sunitinib  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Tacrolimus  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Tamoxifen  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Telaprevir  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Tenecteplase  : May enhance the anticoagulant effect of Anticoagulants.
  •  Tibolone  : May enhance the anticoagulant effect of Anticoagulants.
  •  Tinzaparin  : May enhance the anticoagulant effect of Anticoagulants.
  •  Tipranavir  : May enhance the anticoagulant effect of Anticoagulants.
  •  Treprostinil  : Edoxaban may enhance the anticoagulant effect of Anticoagulants.
  •  Urokinase  : May enhance the anticoagulant effect of Anticoagulants.
  •  Vandetanib  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Vemurafenib  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Verapamil  : P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.
  •  Vitamin E  : May enhance the anticoagulant effect of Anticoagulants. Vitamin E may also increase the overall risk for bleeding.
  •  Vorapaxar  : May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding.
  •  Warfarin  : May enhance the anticoagulant effect of Anticoagulants.

Calculated Property

kind Value Source
logP 1.61 ALOGPS
logS -4.7 ALOGPS
Water Solubility 1.14e-02 g/l ALOGPS
logP 0.9 ChemAxon
IUPAC Name N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-{5-methyl-4H,5H,6H,7H-[1,3]thiazolo[5,4-c]pyridine-2-amido}cyclohexyl]ethanediamide ChemAxon
Traditional IUPAC Name edoxaban ChemAxon
Molecular Weight 548.06 ChemAxon
Monoisotopic Weight 547.1768513 ChemAxon
SMILES CN(C)C(=O)[C@H]1CC[C@H](NC(=O)C(=O)NC2=NC=C(Cl)C=C2)[C@@H](C1)NC(=O)C1=NC2=C(CN(C)CC2)S1 ChemAxon
Molecular Formula C24H30ClN7O4S ChemAxon
InChI InChI=1S/C24H30ClN7O4S/c1-31(2)24(36)13-4-6-15(27-20(33)21(34)30-19-7-5-14(25)11-26-19)17(10-13)28-22(35)23-29-16-8-9-32(3)12-18(16)37-23/h5,7,11,13,15,17H,4,6,8-10,12H2,1-3H3,(H,27,33)(H,28,35)(H,26,30,34)/t13-,15-,17+/m0/s1 ChemAxon
InChIKey HGVDHZBSSITLCT-JLJPHGGASA-N ChemAxon
Polar Surface Area (PSA) 136.63 ChemAxon
Refractivity 140.14 ChemAxon
Polarizability 56.31 ChemAxon
Rotatable Bond Count 6 ChemAxon
H Bond Acceptor Count 7 ChemAxon
H Bond Donor Count 3 ChemAxon
pKa (strongest acidic) 10.74 ChemAxon
pKa (strongest basic) 6.33 ChemAxon
Physiological Charge 0 ChemAxon
Number of Rings 4 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 0 ChemAxon
Ghose Filter 0 ChemAxon
MDDR-Like Rule 1 ChemAxon

Target within organism

  • Coagulation factor X : in Human