Edoxaban

Identification

Summary

Edoxaban is a novel oral anticoagulant used for reducing the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).

Brand Names
Lixiana, Savaysa
Generic Name
Edoxaban
DrugBank Accession Number
DB09075
Background

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.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 548.06
Monoisotopic: 547.1768513
Chemical Formula
C24H30ClN7O4S
Synonyms
  • Edoxaban
External IDs
  • DU 176
  • DU 176b
  • DU-176
  • DU-176b

Pharmacology

Indication

Edoxaban is indicated for reducing 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.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofDeep vein thrombosis••••••••••••
Treatment ofPulmonary embolism••••••••••••
Prophylaxis ofStroke••••••••••••
Prophylaxis ofSystemic embolism••••••••••••
Contraindications & Blackbox Warnings
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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).

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.

TargetActionsOrganism
ACoagulation factor X
inhibitor
Humans
Absorption

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

Volume of distribution

The steady state volume of distribution is 107 L.

Protein binding

In vitro plasma protein binding is ~55%.

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.

Route of elimination

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.

Half-life

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

Clearance

22 L/hr

Adverse Effects
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Toxicity

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.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Edoxaban which could result in a higher serum level.
AbciximabThe risk or severity of bleeding can be increased when Edoxaban is combined with Abciximab.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Edoxaban.
AbrocitinibThe serum concentration of Edoxaban can be increased when it is combined with Abrocitinib.
AceclofenacThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Edoxaban.
Food Interactions
  • Avoid herbs and supplements with anticoagulant/antiplatelet activity. Additive anticoagulant activity may increase the risk of bleeding. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Edoxaban tosylate32W99UE810480449-71-6ZLFZITWZOYXXAW-QXXZOGQOSA-N
Edoxaban tosylate monohydrate972203R4EW1229194-11-9PSMMNJNZVZZNOI-SJILXJHISA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LixianaTablet, film coated30 mgOralDaiichi Sankyo Italia S.P.A.2016-09-08Not applicableEU flag
LixianaTablet, film coated60 mgOralDaiichi Sankyo Italia S.P.A.2016-09-08Not applicableEU flag
LixianaTablet, film coated60 mgOralDaiichi Sankyo Italia S.P.A.2021-01-28Not applicableEU flag
LixianaTablet30 mgOralSERVIER MALAYSIA SDN. BHD.2017-04-25Not applicableCanada flag
LixianaTablet, film coated15 mgOralDaiichi Sankyo Italia S.P.A.2016-09-08Not applicableEU flag

Categories

ATC Codes
B01AF03 — Edoxaban
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as gamma amino acids and derivatives. These are amino acids having a (-NH2) group attached to the gamma carbon atom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Gamma amino acids and derivatives
Alternative Parents
Alpha amino acid amides / 2-heteroaryl carboxamides / Thiazolecarboxamides / N-arylamides / Aralkylamines / Aryl chlorides / Imidolactams / Pyridines and derivatives / Tertiary carboxylic acid amides / Heteroaromatic compounds
show 8 more
Substituents
2-heteroaryl carboxamide / Alpha-amino acid amide / Alpha-amino acid or derivatives / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole
show 24 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
tertiary amino compound, monocarboxylic acid amide, chloropyridine, thiazolopyridine (CHEBI:85973)
Affected organisms
Not Available

Chemical Identifiers

UNII
NDU3J18APO
CAS number
480449-70-5
InChI Key
HGVDHZBSSITLCT-JLJPHGGASA-N
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
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
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

References

General References
  1. Turpie AG: New oral anticoagulants in atrial fibrillation. Eur Heart J. 2008 Jan;29(2):155-65. Epub 2007 Dec 19. [Article]
  2. Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, Kojima M, Kunitada S: Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010 Jul;50(7):743-53. doi: 10.1177/0091270009351883. Epub 2010 Jan 15. [Article]
  3. Yeh CH, Hogg K, Weitz JI: Overview of the new oral anticoagulants: opportunities and challenges. Arterioscler Thromb Vasc Biol. 2015 May;35(5):1056-65. doi: 10.1161/ATVBAHA.115.303397. Epub 2015 Mar 19. [Article]
  4. Senoo K, Lip GY: Comparative efficacy and safety of the non-vitamin K antagonist oral anticoagulants for patients with nonvalvular atrial fibrillation. Semin Thromb Hemost. 2015 Mar;41(2):146-53. doi: 10.1055/s-0035-1544156. Epub 2015 Feb 15. [Article]
  5. Parasrampuria DA, Truitt KE: Pharmacokinetics and Pharmacodynamics of Edoxaban, a Non-Vitamin K Antagonist Oral Anticoagulant that Inhibits Clotting Factor Xa. Clin Pharmacokinet. 2015 Nov 30. [Article]
  6. FDA Approved Drug Products: Savaysa (edoxaban tosylate) tablets for oral use [Link]
KEGG Drug
D09546
PubChem Compound
10280735
PubChem Substance
310265005
ChemSpider
8456212
BindingDB
50328731
RxNav
1599538
ChEBI
85973
ChEMBL
CHEMBL1269025
ZINC
ZINC000043200832
PharmGKB
PA166128806
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Edoxaban
FDA label
Download (600 KB)

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableActive Not RecruitingNot AvailableAtrial Fibrillation2somestatusstop reasonjust information to hide
Not AvailableActive Not RecruitingNot AvailableAtrial Fibrillation or Flutter / Valvular Heart Diseases1somestatusstop reasonjust information to hide
Not AvailableActive Not RecruitingNot AvailableNeoplasm / Systemic Embolism1somestatusstop reasonjust information to hide
Not AvailableActive Not RecruitingNot AvailableNon-valvular Atrial Fibrillation1somestatusstop reasonjust information to hide
Not AvailableActive Not RecruitingTreatmentAtrial Fibrillation / Stroke, Acute1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral15 mg
TabletOral20.210 mg
TabletOral30 mg
TabletOral60 mg
Tablet, coatedOral15 mg
Tablet, film coatedOral
Tablet, coatedOral30 mg
Tablet, coatedOral60 mg
Tablet, film coatedOral15 mg
Tablet, film coatedOral30 mg
Tablet, film coatedOral60 mg
Tablet, film coatedOral15 mg/1
Tablet, film coatedOral30 mg/1
Tablet, film coatedOral60 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US2013026553No2011-08-222031-08-22US flag
US9149532No2015-10-062028-03-28US flag
US7365205No2008-04-292023-06-12US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
pKa6.7FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.0114 mg/mLALOGPS
logP1.61ALOGPS
logP0.9Chemaxon
logS-4.7ALOGPS
pKa (Strongest Acidic)10.74Chemaxon
pKa (Strongest Basic)6.33Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area136.63 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity140.14 m3·mol-1Chemaxon
Polarizability56.31 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00dj-0300970000-af33c06cd00ce6106d57
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-6019000000-82bef3e8398a6f03b755
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-001j-0902070000-f8996728749f042d1628
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-00kg-8239160000-422da7617fce7b314980
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-002b-0933270000-36f2545cadfb3e3d4e8c
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9612140000-63039fc10c1ceb3d60dd
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-217.6334
predicted
DeepCCS 1.0 (2019)
[M+H]+219.52882
predicted
DeepCCS 1.0 (2019)
[M+Na]+225.3137
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting. Factor Xa activates pro-inflammatory signaling pathways in a protease-activated receptor (PAR)-dependent manner (PubMed:24041930, PubMed:30568593, PubMed:34831181). Up-regulates expression of protease-activated receptors (PARs) F2R, F2RL1 and F2RL2 in dermal microvascular endothelial cells (PubMed:35738824). Triggers the production of pro-inflammatory cytokines, such as MCP-1/CCL2 and IL6, in cardiac fibroblasts and umbilical vein endothelial cells in PAR-1 (F2R)-dependent manner (PubMed:30568593, PubMed:34831181). Triggers the production of pro-inflammatory cytokines, such as MCP-1/CCL2, IL6, TNF-alpha/TNF, IL-1beta/IL1B, IL8/CXCL8 and IL18, in endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824, PubMed:9780208). Induces expression of adhesion molecules, such as ICAM1, VCAM1 and SELE, in endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824, PubMed:9780208). Increases expression of phosphorylated ERK1/2 in dermal microvascular endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824). Triggers activation of the transcription factor NF-kappa-B in dermal microvascular endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824). Up-regulates expression of plasminogen activator inhibitor 1 (SERPINE1) in atrial tissues (PubMed:24041930)
Specific Function
calcium ion binding
Gene Name
F10
Uniprot ID
P00742
Uniprot Name
Coagulation factor X
Molecular Weight
54731.255 Da
References
  1. Turpie AG: New oral anticoagulants in atrial fibrillation. Eur Heart J. 2008 Jan;29(2):155-65. Epub 2007 Dec 19. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function
ABC-type xenobiotic transporter activity
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
ATP-dependent translocase ABCB1
Molecular Weight
141477.255 Da
References
  1. Mikkaichi T, Yoshigae Y, Masumoto H, Imaoka T, Rozehnal V, Fischer T, Okudaira N, Izumi T: Edoxaban transport via P-glycoprotein is a key factor for the drug's disposition. Drug Metab Dispos. 2014 Apr;42(4):520-8. doi: 10.1124/dmd.113.054866. Epub 2014 Jan 23. [Article]

Drug created at May 15, 2015 16:35 / Updated at October 11, 2024 17:54