Edoxaban

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Edoxaban
Edoxaban.svg
Clinical data
Trade names Savaysa, Lixiana, Roteas, others
Other namesDU-176b
AHFS/Drugs.com Monograph
MedlinePlus a614055
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 62%; Tmax 1–2 hours [4]
Protein binding 55% [4]
Metabolism minimal CES1, CYP3A4/5, hydrolysis, glucuronidation [4]
Elimination half-life 10–14 hours [4]
Excretion 62% feces, 35% urine
Identifiers
  • 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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
Formula C24H30ClN7O4S
Molar mass 548.06 g·mol−1
3D model (JSmol)
  • CN1CCC2=C(C1)SC(=N2)C(=O)N[C@@H]3C[C@H](CC[C@@H]3NC(=O)C(=O)NC4=NC=C(C=C4)Cl)C(=O)N(C)C
  • 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 X mark.svgN
  • Key:HGVDHZBSSITLCT-JLJPHGGASA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Edoxaban, sold under the brand name Lixiana among others, is an anticoagulant medication and a direct factor Xa inhibitor. [1] It is taken by mouth. [1]

Contents

Compared with warfarin it has fewer drug interactions. [4]

It was developed by Daiichi Sankyo and approved in July 2011, in Japan for prevention of venous thromboembolisms following lower-limb orthopedic surgery. [5] It was also approved in the United States by the Food and Drug Administration (FDA) in January 2015, for the prevention of stroke and non–central-nervous-system systemic embolism. [6] [7] It was approved for use in the European Union in June 2015. [2] It is on the World Health Organization's List of Essential Medicines. [8]

Medical uses

In the United States, edoxaban is indicated to treat deep vein thrombosis and pulmonary embolism following five to ten days of initial therapy with a parenteral anticoagulant. [1] It is also indicated to reduce the risk of blood clots in people with nonvalvular atrial fibrillation. [1] [9]

In the European Union, edoxaban is indicated for preventing blood clots in people with nonvalvular atrial fibrillation who also have at least one risk factor, such as having had a previous stroke, high blood pressure (hypertension), diabetes mellitus, congestive heart failure or being 75 years of age or older. It is also used to treat deep vein thrombosis and pulmonary embolism and to prevent either of these from reoccurring. [2]

Contraindications and notes

Edoxaban is often contraindicated in people (incomplete list):

Edoxaban (incomplete list):

Adverse effects

May affect up to 1 in 10 people: [10]

May affect up to 1 in 100 people: [10]

May affect up to 1 in 1000 people: bleeding in the muscles, joints, abdomen, heart or inside the skull. [10]

Overdose

Edoxaban overdose can cause serious bleeding. [2] No approved antidotes for edoxaban overdose exist as of April 2021. [2] Hemodialysis does not significantly contribute to edoxaban clearance. [1] [10] Andexanet alfa has been studied as an antidote for edoxaban overdose, but has only been approved for reversing rivaroxaban and apixaban effects by the FDA and the EMA as of 2019. [11] [12]

Mechanism of action

Edoxaban is a direct, selective, reversible and competitive inhibitor of human factor Xa, with an inhibitory constant (Ki) value of 0.561 nM. In coagulation, uninhibited factor Xa forms a prothrombinase complex with factor Va on platelet surfaces. Prothrombinases turn prothrombins to thrombins. Thrombins turn blood-soluble fibrinogens to insoluble fibrins, which are the main components of blood clots. [4]

Pharmacokinetics

In human, 15–150 mg oral doses of edoxaban reach their maximum concentrations in blood 1–2 hours after ingestion. With 60 mg doses of isotope labeled edoxaban, 97% of the total radiation was detected after oral administration, with 62% from feces and 35% from urine. 49% of the total radiation from the feces and 24% from the urine were from edoxaban, the rest from its metabolites. [4]

Metabolism occurs mostly via CES1, CYP3A4, CYP3A5 and enzymatic hydrolysis. CES1 oxidizes the tertiary amide carbonyl carbons of edoxabans to carboxylic acid groups. CYP3A4 and CYP3A5 oxidize edoxabans via hydroxylation or demethylation. In hydrolysis, 2-amino-5-chloropyridine moiety of edoxaban is removed. Glucuronidation occurs to a lesser extent via glucuronosyltransferases. [4]

Related Research Articles

Anticoagulant Class of drugs

Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the bite area unclotted long enough for the animal to obtain some blood. As a class of medications, anticoagulants are used in therapy for thrombotic disorders. Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals. Some anticoagulants are used in medical equipment, such as sample tubes, blood transfusion bags, heart-lung machines, and dialysis equipment. One of the first anticoagulants, warfarin, was initially approved as a rodenticide.

Warfarin Medication used as an anticoagulant

Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant. It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent stroke in people who have atrial fibrillation, valvular heart disease or artificial heart valves. Less commonly it is used following ST-segment elevation myocardial infarction (STEMI) and orthopedic surgery. It is generally taken by mouth, but may also be used by injection into a vein.

Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and treatment of venous thromboembolism and in the treatment of myocardial infarction.

Ximelagatran

Ximelagatran is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would withdraw pending applications for marketing approval after reports of hepatotoxicity during trials, and discontinue its distribution in countries where the drug had been approved.

Enoxaparin sodium Anticoagulant medication (blood thinner)

Enoxaparin sodium is an anticoagulant medication. It is used to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE) including during pregnancy and following certain types of surgery. It is also used in those with acute coronary syndrome (ACS) and heart attacks. It is given by injection just under the skin or into a vein. It is also used during hemodialysis.

Rivaroxaban Anticoagulant drug

Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication used to treat and prevent blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery. It is taken by mouth.

Dalteparin sodium Pharmaceutical drug

Dalteparin is a low molecular weight heparin. It is marketed as Fragmin. Like other low molecular weight heparins, dalteparin is used for prophylaxis or treatment of deep vein thrombosis and pulmonary embolism to reduce the risk of a stroke or heart attack. Dalteparin acts by potentiating the activity of antithrombin III, inhibiting formation of both Factor Xa and thrombin. It is normally administered by self-injection.

Phenprocoumon Drug

Phenprocoumon is a long-acting blood thinner drug to be taken by mouth, and a derivative of coumarin. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) by blocking synthesis of coagulation factors II, VII, IX and X. It is used for the prophylaxis and treatment of thromboembolic disorders such as heart attacks and pulmonary (lung) embolism. The most common adverse effect is bleeding. The drug interacts with a large number of other medications, including aspirin and St John's Wort. It is the standard coumarin used in Germany, Austria, and other European countries.

Dabigatran Anticoagulant medication

Dabigatran, sold under the brand name Pradaxa among others, is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation. Specifically it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. It is used as an alternative to warfarin and does not require monitoring by blood tests. It is taken by mouth.

Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis. Pregnancy itself is a factor of hypercoagulability, as a physiologically adaptive mechanism to prevent post partum bleeding. However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.

Direct factor Xa inhibitors (xabans) are anticoagulants, used to both treat and prevent blood clots in veins, and prevent stroke and embolism in people with atrial fibrillation (AF).

Vitamin K antagonist

Vitamin K antagonists (VKA) are a group of substances that reduce blood clotting by reducing the action of vitamin K. The term "vitamin K antagonist" is technically a misnomer, as the drugs do not directly antagonise the action of vitamin K in the pharmacological sense, but rather the recycling of vitamin K.

The management of atrial fibrillation (AF) is focused on preventing temporary circulatory instability, stroke and other ischemic events. Control of heart rate and rhythm are principally used to achieve the former, while anticoagulation may be employed to decrease the risk of stroke. Within the context of stroke, the discipline may be referred to as stroke prevention in atrial fibrillation (SPAF). In emergencies, when circulatory collapse is imminent due to uncontrolled rapid heart rate, immediate cardioversion may be indicated.

Betrixaban

Betrixaban is an oral anticoagulant drug which acts as a direct factor Xa inhibitor. Betrixaban is FDA approved for venous thrombosis prevention in adults hospitalized for an acute illness who are at risk for thromboembolic complications. Compared to other directly acting oral anticoagulants betrixaban has relatively low renal excretion and is not metabolized by CYP3A4.

Apixaban Anticoagulant medication

Apixaban, sold under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor Xa. Specifically it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. It is used as an alternative to warfarin and does not require monitoring by blood tests or dietary restrictions. It is taken by mouth.

Darexaban Chemical compound

Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma. It is an experimental drug that acts as an anticoagulant and antithrombotic to prevent venous thromboembolism after a major orthopaedic surgery, stroke in patients with atrial fibrillation and possibly ischemic events in acute coronary syndrome. It is used in form of the maleate. The development of darexaban was discontinued in September 2011.

Direct thrombin inhibitors (DTIs) are a class of anticoagulant drugs that can be used to prevent and treat embolisms and blood clots caused by various diseases. They inhibit thrombin, a serine protease which affects the coagulation cascade in many ways. DTIs have undergone rapid development since the 90's. With technological advances in genetic engineering the production of recombinant hirudin was made possible which opened the door to this new group of drugs. Before the use of DTIs the therapy and prophylaxis for anticoagulation had stayed the same for over 50 years with the use of heparin derivatives and warfarin which have some well known disadvantages. DTIs are still under development, but the research focus has shifted towards factor Xa inhibitors, or even dual thrombin and fXa inhibitors that have a broader mechanism of action by both inhibiting factor IIa (thrombin) and Xa. A recent review of patents and literature on thrombin inhibitors has demonstrated that the development of allosteric and multi-mechanism inhibitors might lead the way to a safer anticoagulant.

Andexanet alfa, sold under the trade name Andexxa among others, is an antidote for the medications rivaroxaban and apixaban, when reversal of anticoagulation is needed due to uncontrolled bleeding. It has not been found to be useful for other factor Xa inhibitors. It is given by injection into a vein.

Four drugs from the class of direct Xa inhibitors are marketed worldwide. Rivaroxaban (Xarelto) was the first approved FXa inhibitor to become commercially available in Europe and Canada in 2008. The second one was apixaban (Eliquis), approved in Europe in 2011 and in the United States in 2012. The third one edoxaban was approved in Japan in 2011 and in Europe and the US in 2015. Betrixaban (Bevyxxa) was approved in the US in 2017.

Portola Pharmaceuticals is an American clinical stage biotechnology company that researches, develops, and commercializes drugs. The company focuses primarily on drugs used in the treatment of thrombosis and hematological malignancies.

References

  1. 1 2 3 4 5 6 7 "Savaysa- edoxaban tosylate tablet, film coated". DailyMed. 24 April 2020. Retrieved 23 July 2020.
  2. 1 2 3 4 5 "Lixiana EPAR". European Medicines Agency (EMA). Retrieved 23 July 2020.
  3. ↑ "Roteas EPAR". European Medicines Agency (EMA). Retrieved 25 September 2020.
  4. 1 2 3 4 5 6 7 8 Parasrampuria DA, Truitt KE (June 2016). "Pharmacokinetics and Pharmacodynamics of Edoxaban, a Non-Vitamin K Antagonist Oral Anticoagulant that Inhibits Clotting FactorXa". Clinical Pharmacokinetics. 55 (6): 641–55. doi:10.1007/s40262-015-0342-7. PMC   4875962 . PMID   26620048.
  5. ↑ "First market approval in Japan for Lixiana (Edoxaban)". Daiichi Sankyo Europe GmbH (Press release). 22 April 2011. Archived from the original on 6 November 2013.
  6. ↑ O'Riordan M (9 January 2015). "FDA Approves Edoxaban for Stroke Prevention in AF and DVT/PE Prevention". Medscape. Retrieved 10 January 2015.
  7. ↑ "Drug Approval Package: Savaysa (edoxaban tosylate) Tablets NDA #206316". U.S. Food and Drug Administration (FDA). 13 February 2015. Retrieved 23 July 2020.
  8. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl: 10665/345533 . WHO/MHP/HPS/EML/2021.02.
  9. ↑ Lowenstern A, Al-Khatib SM, Sharan L, Chatterjee R, Allen LaPointe NM, Shah B, et al. (December 2018). "Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation: A Systematic Review". Annals of Internal Medicine. 169 (11): 774–787. doi: 10.7326/M18-1523 . PMC   6825839 . PMID   30383133.
  10. 1 2 3 4 5 6 7 8 9 10 11 "Lixiana, INN-edoxaban" (PDF). Archived (PDF) from the original on 6 November 2019. Retrieved 6 November 2019.
  11. ↑ Ovanesov M (3 August 2017). "Summary basis for regulatory action - ANDEXXA". Food and Drug Administration . Retrieved 6 November 2019.
  12. ↑ "Ondexxya". European Medicines Agency. 27 February 2019. Archived from the original on 16 July 2019. Retrieved 6 November 2019.
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