Identification

Name
Edoxaban
Accession Number
DB09075
Type
Small Molecule
Groups
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.

Structure
Thumb
Synonyms
  • Edoxaban
External IDs
DU 176 / DU 176b / DU-176 / DU-176b
Product Ingredients
IngredientUNIICASInChI Key
Edoxaban tosylate32W99UE810480449-71-6ZLFZITWZOYXXAW-QXXZOGQOSA-N
Edoxaban tosylate monohydrate972203R4EW1229194-11-9PSMMNJNZVZZNOI-SJILXJHISA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
LixianaTablet, film coated15 mgOralDaiichi Sankyo Europe, Gmb H2015-06-19Not applicableEu
LixianaTablet, film coated30 mgOralDaiichi Sankyo Europe, Gmb H2015-06-19Not applicableEu
LixianaTablet, film coated30 mgOralDaiichi Sankyo Europe, Gmb H2015-06-19Not applicableEu
LixianaTablet, film coated60 mgOralDaiichi Sankyo Europe, Gmb H2015-06-19Not applicableEu
LixianaTablet, film coated60 mgOralDaiichi Sankyo Europe, Gmb H2015-06-19Not applicableEu
LixianaTablet60 mgOralServier2017-04-25Not applicableCanada
LixianaTablet, film coated60 mgOralDaiichi Sankyo Europe, Gmb H2015-06-19Not applicableEu
LixianaTablet, film coated30 mgOralDaiichi Sankyo Europe, Gmb H2015-06-19Not applicableEu
LixianaTablet, film coated30 mgOralDaiichi Sankyo Europe, Gmb H2015-06-19Not applicableEu
LixianaTablet, film coated60 mgOralDaiichi Sankyo Europe, Gmb H2015-06-19Not applicableEu
International/Other Brands
Lixiana (Daiichi-Sankyo)
Categories
UNII
NDU3J18APO
CAS number
480449-70-5
Weight
Average: 548.06
Monoisotopic: 547.1768513
Chemical Formula
C24H30ClN7O4S
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

Pharmacology

Indication

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.

Associated Conditions
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
Human
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

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.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Edoxaban which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Edoxaban which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Edoxaban which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Edoxaban which could result in a lower serum level and potentially a reduction in efficacy.
AclidiniumAclidinium may decrease the excretion rate of Edoxaban which could result in a higher serum level.
AcrivastineEdoxaban may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Edoxaban which could result in a higher serum level.
AdefovirAdefovir may decrease the excretion rate of Edoxaban which could result in a higher serum level.
Adefovir DipivoxilAdefovir Dipivoxil may decrease the excretion rate of Edoxaban which could result in a higher serum level.
Albutrepenonacog alfaEdoxaban may decrease the excretion rate of Albutrepenonacog alfa which could result in a higher serum level.
Food Interactions
Not Available

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. [PubMed:18096568]
  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. [PubMed:20081065]
  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. [PubMed:25792448]
  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. [PubMed:25682085]
  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. [PubMed:26620048]
External Links
KEGG Drug
D09546
PubChem Compound
10280735
PubChem Substance
310265005
ChemSpider
8456212
BindingDB
50328731
ChEBI
85973
ChEMBL
CHEMBL1269025
PharmGKB
PA166128806
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Edoxaban
AHFS Codes
  • 20:12.04.14 — Direct Factor Xa Inhibitors
FDA label
Download (600 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedSupportive CareHaemorrhage1
1CompletedTreatmentHaemorrhage1
1RecruitingBasic ScienceDeep Vein Thrombosis (DVT) / Venous Thromboembolism (VTE) / Venous Thrombosis Pediatrics1
2CompletedOtherAnticoagulation Reversal / Healthy Volunteers1
2CompletedPreventionArthroplasty, Replacement, Hip / Deep Vein Thrombosis (DVT) / Embolism and Thrombosis / Thromboembolism / Thrombotic events / Venous Thromboembolism (VTE)1
2CompletedPreventionArthroplasty, Replacement, Hip / Thrombotic events1
2CompletedPreventionDeep Vein Thrombosis (DVT) / Total Knee Arthroplasty (TKA) / Venous Thromboembolism (VTE)1
2CompletedPreventionNonvalvular Atrial Fibrillation1
2CompletedPreventionNonvalvular Atrial Fibrillation / Strokes1
2CompletedPreventionNonvalvular Atrial Fibrillation / Thromboembolism1
2CompletedTreatmentDeep Vein Thrombosis (DVT) / Thrombosis, Venous1
2CompletedTreatmentHealthy Volunteers1
2CompletedTreatmentPeripheral Arterial Disease (PAD)1
2RecruitingPreventionAcute Ischemic Stroke (AIS)1
2RecruitingTreatmentHaemorrhage1
2, 3RecruitingTreatmentCorrection of Cancer-related Coagulopathy With Novel Oral Anticoagulant (Edoxaban)1
2, 3Unknown StatusTreatmentCerebral Infarctions / Strokes / Transient ischemia attacks1
3Active Not RecruitingTreatmentNonvalvular Atrial Fibrillation1
3CompletedPreventionNon-valvular Atrial Fibrillation (NVAF)1
3CompletedPreventionNonvalvular Atrial Fibrillation / Strokes / Systemic Embolism1
3CompletedPreventionPrevention / Venous Thromboembolism (VTE)1
3CompletedPreventionVenous Thromboembolism (VTE)3
3CompletedTreatmentDeep Vein Thrombosis (DVT) / Malignancies / Pulmonary Embolism (PE) / Venous Thromboembolism (VTE)1
3CompletedTreatmentDeep Vein Thrombosis (DVT) / Pulmonary Embolism (PE) / Thromboembolism / Thrombosis, Venous / Venous Thromboembolism (VTE)1
3CompletedTreatmentNonvalvular Atrial Fibrillation1
3RecruitingPreventionAnticoagulant Drugs / Cardiac Diseases1
3RecruitingPreventionAtrial Flutter / Intracranial Hemorrhage, Hypertensive / Intracranial Hemorrhages / Intraventricular Hemorrhage / Microhaemorrhage / Nonvalvular Atrial Fibrillation / Small Vessel Cerebrovascular Disease / Subarachnoid Hemorrhage / Subdural haematoma1
3RecruitingPreventionAtrial High Rate Episodes1
3RecruitingPreventionNonvalvular Atrial Fibrillation1
3RecruitingTreatmentDeep Vein Thrombosis (DVT) / Pulmonary Embolism (PE) / Venous Thromboembolism (VTE)1
3RecruitingTreatmentMV(Mitral Valve) Repair1
3RecruitingTreatmentNonvalvular Atrial Fibrillation2
4CompletedTreatmentCoronary Artery Disease1
4Not Yet RecruitingBasic ScienceDisorders, Blood Coagulation1
4Not Yet RecruitingTreatmentChronic Stable Angina Pectoris / Coronary Artery Disease / Nonvalvular Atrial Fibrillation / Stable Angina (SA)1
4Not Yet RecruitingTreatmentLeft Atrial Appendage Closure / Non-valvular Atrial Fibrillation (NVAF)1
4Not Yet RecruitingTreatmentNonvalvular Atrial Fibrillation / Stroke, Acute1
4RecruitingPreventionNonvalvular Atrial Fibrillation2
4RecruitingTreatmentDeep Vein Thrombosis (DVT) / Pulmonary Embolism (PE)1
4RecruitingTreatmentDiabetes Mellitus (DM)1
4TerminatedTreatmentNonvalvular Atrial Fibrillation1
Not AvailableActive Not RecruitingNot AvailableNonvalvular Atrial Fibrillation3
Not AvailableActive Not RecruitingNot AvailableVenous Thromboembolism (VTE)1
Not AvailableActive Not RecruitingBasic ScienceNonvalvular Atrial Fibrillation1
Not AvailableCompletedNot AvailableHealthy Volunteers1
Not AvailableCompletedNot AvailableNonvalvular Atrial Fibrillation1
Not AvailableEnrolling by InvitationTreatmentAcute DVT of Lower Extremity1
Not AvailableRecruitingNot AvailableAnticoagulants and Bleeding Disorders / Venous Thromboembolism (VTE)1
Not AvailableRecruitingNot AvailableHeart Failure, Unspecified1
Not AvailableRecruitingNot AvailableNonvalvular Atrial Fibrillation2
Not AvailableRecruitingNot AvailableVenous Thromboembolism (VTE)1
Not AvailableRecruitingHealth Services ResearchNeoplasms / Thrombosis, Venous1
Not AvailableRecruitingPreventionNonvalvular Atrial Fibrillation / Strokes1
Not AvailableRecruitingTreatmentBlood Clots / Deep Vein Thrombosis (DVT) / Malignancies / Pulmonary Embolism (PE) / Venous Thromboembolism (VTE)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral15 mg
TabletOral30 mg
TabletOral60 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)
US2013026553No2011-08-222031-08-22Us
US9149532No2015-10-062028-03-28Us
US7365205No2008-04-292023-06-12Us

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/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Alpha-amino acid amide / Gamma amino acid or derivatives / Alpha-amino acid or derivatives / 2-heteroaryl carboxamide / Thiazolecarboxamide / Thiazolecarboxylic acid or derivatives / N-arylamide / Aralkylamine / Aryl chloride / Aryl halide
show 24 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
tertiary amino compound, monocarboxylic acid amide, chloropyridine, thiazolopyridine (CHEBI:85973)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type endopeptidase activity
Specific 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.
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. [PubMed:18096568]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
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. [PubMed:24459178]

Drug created on May 15, 2015 10:35 / Updated on December 16, 2018 07:04