Entecavir

Identification

Name
Entecavir
Accession Number
DB00442  (APRD00948)
Type
Small Molecule
Groups
Approved, Investigational
Description

Entecavir is an oral antiviral drug used in the treatment of hepatitis B infection. It is marketed under the trade name Baraclude (BMS).

Entecavir is a guanine analogue that inhibits all three steps in the viral replication process, and the manufacturer claims that it is more efficacious than previous agents used to treat hepatitis B (lamivudine and adefovir). It was approved by the U.S. Food and Drug Administration (FDA) in March 2005.

Structure
Thumb
Synonyms
  • Anhydrous entecavir
  • Entecavir
  • Entecavir (anhydrous)
  • Entecavir anhydrous
  • Entecavirum
External IDs
BMS-200475-01 / ETV / SQ34676
Product Ingredients
IngredientUNIICASInChI Key
Entecavir monohydrate5968Y6H45M209216-23-9YXPVEXCTPGULBZ-WQYNNSOESA-N
Entecavir triphosphateNot AvailableNot AvailableNot applicable
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BaracludeTablet, film coated1 mgOralBristol Myers Squibb Pharma Eeig2006-06-26Not applicableEu
BaracludeTablet0.5 mgOralBristol Myers Squibb2006-09-12Not applicableCanada
BaracludeSolution0.05 mg/1mLOralE.R. Squibb & Sons, L.L.C.2005-03-29Not applicableUs
BaracludeTablet, film coated1 mgOralBristol Myers Squibb Pharma Eeig2006-06-26Not applicableEu
BaracludeTablet, film coated1 mgOralBristol Myers Squibb Pharma Eeig2006-06-26Not applicableEu
BaracludeTablet, film coated0.5 mgOralBristol Myers Squibb Pharma Eeig2006-06-26Not applicableEu
BaracludeTablet, film coated1.0 mg/1OralE.R. Squibb & Sons, L.L.C.2005-03-29Not applicableUs
BaracludeTablet, film coated0.5 mgOralBristol Myers Squibb Pharma Eeig2006-06-26Not applicableEu
BaracludeTablet, film coated0.5 mgOralBristol Myers Squibb Pharma Eeig2006-06-26Not applicableEu
BaracludeTablet, film coated0.5 mg/1OralE.R. Squibb & Sons, L.L.C.2005-03-29Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-entecavirTablet0.5 mgOralApotex Corporation2013-01-18Not applicableCanada
Auro-entecavirTablet0.5 mgOralAuro Pharma Inc2015-12-01Not applicableCanada
EntecavirTablet, film coated0.5 mg/1OralAccord Healthcare Limited2017-08-25Not applicableUs
EntecavirTablet0.5 mg/1OralAurobindo Pharma2015-08-26Not applicableUs
EntecavirTablet, film coated0.5 mg/1OralAmneal Pharmaceuticals2014-11-28Not applicableUs
EntecavirTablet, film coated0.5 mg/1OralGolden State Medical Supply Inc.2017-08-25Not applicableUs
EntecavirTablet, film coated1.0 mg/1OralPar Pharmaceutical2014-08-182017-08-31Us
EntecavirTablet, coated0.5 mg/1OralPar Pharmaceutical2017-03-29Not applicableUs
EntecavirTablet1 mg/1OralLucid Pharma Llc2017-02-06Not applicableUs
EntecavirTablet0.5 mg/1OralBreckenridge Pharmaceutical, Inc.2018-03-16Not applicableUs
International/Other Brands
Barcavir (Incepta) / Caavirel (PMP) / Entaliv (Dr. Reddy's Laboratories) / Teviral (ACI)
Categories
UNII
NNU2O4609D
CAS number
142217-69-4
Weight
Average: 277.2792
Monoisotopic: 277.117489371
Chemical Formula
C12H15N5O3
InChI Key
QDGZDCVAUDNJFG-FXQIFTODSA-N
InChI
InChI=1S/C12H15N5O3/c1-5-6(3-18)8(19)2-7(5)17-4-14-9-10(17)15-12(13)16-11(9)20/h4,6-8,18-19H,1-3H2,(H3,13,15,16,20)/t6-,7-,8-/m0/s1
IUPAC Name
2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-6,9-dihydro-3H-purin-6-one
SMILES
NC1=NC(=O)C2=C(N1)N(C=N2)[C@H]1C[C@H](O)[C@@H](CO)C1=C

Pharmacology

Indication

For the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

Associated Conditions
Pharmacodynamics

Entecavir is a guanosine nucleoside analogue with selective activity against hepatitis B virus (HBV). It is designed to selectively inhibit the Hepatitis B virus, blocking all three steps in the replication process. Entecavir is more efficient than an older Hepatitis B drug, lamivudine.

Mechanism of action

By competing with the natural substrate deoxyguanosine triphosphate, entecavir functionally inhibits all three activities of the HBV polymerase (reverse transcriptase, rt): (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Upon activation by kinases, the drug can be incorporated into the DNA which has the ultimate effect of inhibiting the HBV polymerase activity.

TargetActionsOrganism
ADNA
other
Human
Absorption

Absorption Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours. In healthy subjects, the bioavailability of the tablet is 100% relative to the oral solution.

Volume of distribution
Not Available
Protein binding

Binding of entecavir to human serum proteins in vitro is approximately 13%.

Metabolism

Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. Entecavir is efficiently phosphorylated to the active triphosphate form.

Route of elimination
Not Available
Half life

After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128-149 hours. The phosphorylated metabolite has a half-life of 15 hours.

Clearance
  • renal cl=383.2 +/- 101.8 mL/min [Unimpaired renal function]
  • renal cl=197.9 +/- 78.1 mL/min [Mild impaired renal function]
  • renal cl=135.6 +/- 31.6 mL/min [Moderate impaired renal function]
  • renal cl=40.3 +/- 10.1 mL/min [severe impaired renal function]
  • apparent oral cl=588.1 +/- 153.7 mL/min [Unimpaired renal function]
  • apparent oral cl=309.2 +/- 62.6 mL/min [Mild impaired renal function]
  • apparent oral cl=226.3 +/- 60.1 mL/min [Moderate impaired renal function]
  • apparent oral cl=100.6 +/- 29.1 mL/min [severe impaired renal function]
  • apparent oral cl=50.6 +/- 16.5 mL/min [severe impaired renal function amnaged with Hemodialysis]
  • apparent oral cl=35.7 +/- 19.6 mL/min [severe impaired renal function amnaged with CAPD]
Toxicity

Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase in or unexpected adverse events. If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Affected organisms
  • Hepatitis B virus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Entecavir.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be increased when it is combined with Entecavir.
6-O-benzylguanineThe serum concentration of 6-O-benzylguanine can be increased when it is combined with Entecavir.
7-DeazaguanineThe serum concentration of 7-Deazaguanine can be increased when it is combined with Entecavir.
7,9-DimethylguanineThe serum concentration of 7,9-Dimethylguanine can be increased when it is combined with Entecavir.
8-azaguanineThe serum concentration of 8-azaguanine can be increased when it is combined with Entecavir.
8-chlorotheophyllineThe serum concentration of 8-chlorotheophylline can be increased when it is combined with Entecavir.
9-DeazaguanineThe serum concentration of 9-Deazaguanine can be increased when it is combined with Entecavir.
9-MethylguanineThe serum concentration of 9-Methylguanine can be increased when it is combined with Entecavir.
AbirateroneThe serum concentration of Entecavir can be increased when it is combined with Abiraterone.
Food Interactions
  • Take on an empty stomach.
  • Taking the product with a high-fat meal or a light snack reduces the maximal concentration by 44 to 46% and total exposure by 18 to 20%.

References

Synthesis Reference
US5206244
General References
Not Available
External Links
Human Metabolome Database
HMDB0014585
KEGG Drug
D04008
PubChem Compound
153941
PubChem Substance
46504864
ChemSpider
135679
ChEBI
473990
ChEMBL
CHEMBL713
Therapeutic Targets Database
DAP000697
PharmGKB
PA164784025
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Entecavir
ATC Codes
J05AF10 — Entecavir
AHFS Codes
  • 08:18.32 — Nucleosides and Nucleotides
FDA label
Download (628 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHBV1
1CompletedTreatmentHepatitis B Chronic Infection4
1CompletedTreatmentHepatitis B Virus (HBV)1
1CompletedTreatmentViral Hepatitis B1
1RecruitingTreatmentHepatitis B Chronic Infection1
1TerminatedTreatmentHepatitis B Chronic Infection / Viral Hepatitis B1
1TerminatedTreatmentViral Hepatitis B1
1, 2CompletedTreatmentHepatitis B Chronic Infection3
1, 2Not Yet RecruitingTreatmentHepatitis B Chronic Infection1
1, 2Unknown StatusTreatmentHepatitis B Chronic Infection1
2CompletedTreatmentHBV / Hepatitis B Virus (HBV)1
2CompletedTreatmentHepatic Failure1
2CompletedTreatmentHepatitis B Chronic Infection8
2CompletedTreatmentHepatitis B Virus (HBV)1
2RecruitingTreatmentHepatitis B Chronic Infection3
2RecruitingTreatmentNeoplasms, Colorectal1
2RecruitingTreatmentStomach Neoplasms1
2TerminatedTreatmentHepatitis B Chronic Infection1
2TerminatedTreatmentHepatitis D / Viral Hepatitis B1
2TerminatedTreatmentLiver Fibrosis Due to Chronic Hepatitis B Infection1
2Unknown StatusPreventionNon-Hodgkin's Lymphoma (NHL) / Reactivation of hepatitis B virus infection1
2Unknown StatusTreatmentHepatitis B Chronic Infection1
2, 3CompletedTreatmentLiver Cancer1
2, 3CompletedTreatmentViral Hepatitis B1
2, 3RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection / HBV Coinfection / Reactivation of hepatitis B virus infection1
2, 3RecruitingTreatmentHepatocellular,Carcinoma1
3CompletedPreventionHepatitis B Chronic Infection1
3CompletedTreatmentAntiviral Treatment of Chronic Hepatitis B1
3CompletedTreatmentChronic Hepatitis B Virus1
3CompletedTreatmentChronic Hepatitis B Virus, Pediatric1
3CompletedTreatmentChronic Viral Hepatitis B Without Delta-agent1
3CompletedTreatmentDisease, Chronic / Viral Hepatitis B1
3CompletedTreatmentHepatitis B Chronic Infection7
3CompletedTreatmentHepatitis B Chronic Infection / Viral Hepatitis B1
3CompletedTreatmentHuman Immunodeficiency Virus (HIV)1
3CompletedTreatmentLiver Diseases / Transplantation, Liver / Viral Hepatitis B1
3CompletedTreatmentMalignancies / Viral Hepatitis B1
3CompletedTreatmentViral Hepatitis B2
3RecruitingTreatmentHepatitis B Chronic Infection2
3TerminatedPreventionAnkylosing Spondylitis (AS) / Hepatitis B Chronic Infection / Juvenile Idiopathic Arthritis (JIA) / Psoriatic Arthritis / Rheumatoid Arthritis1
3TerminatedTreatmentHepatitis B Chronic Infection1
3TerminatedTreatmentViral Hepatitis B1
3Unknown StatusTreatmentHepatitis B Chronic Infection1
4Active Not RecruitingTreatmentHepatitis B Chronic Infection2
4CompletedPreventionNon Hodgkin Lymphoma (NHL) / Viral Hepatitis B1
4CompletedTreatmentChronic Viral Hepatitis B Without Delta-agent2
4CompletedTreatmentFibrosis, Liver1
4CompletedTreatmentHepatitis B Chronic Infection15
4CompletedTreatmentHepatitis B Infection1
4CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Viral Hepatitis B1
4CompletedTreatmentLiver Cirrhosis2
4CompletedTreatmentViral Hepatitis B1
4Enrolling by InvitationTreatmentHepatitis B Chronic Infection1
4Not Yet RecruitingOtherHepatitis B Chronic Infection1
4Not Yet RecruitingTreatmentAcute-On-Chronic Liver Failure / Viral Hepatitis B / Virus Diseases1
4Not Yet RecruitingTreatmentHepatitis B Chronic Infection / Liver Inflammation1
4Not Yet RecruitingTreatmentPortal Hypertension2
4RecruitingPreventionExposure to Hepatitis B Virus / Reactivation of hepatitis B virus infection / Rheumatoid Arthritis1
4RecruitingTreatmentHepatitis B Chronic Infection11
4RecruitingTreatmentHepatitis B Virus Associated Nephrotic Syndrome1
4RecruitingTreatmentLiver Cirrhosis Due to Hepatitis B Virus1
4RecruitingTreatmentLiver Cirrhosis / Viral Hepatitis B1
4RecruitingTreatmentViral Hepatitis B2
4TerminatedNot AvailableFibrosis, Liver / Hepatitis B Chronic Infection1
4TerminatedDiagnosticLactic Acidosis1
4TerminatedTreatmentHepatitis B Chronic Infection2
4Unknown StatusPreventionHepatitis / HepatitisB / Tuberculosis Infection1
4Unknown StatusTreatmentCirrhosis Due to Hepatitis B1
4Unknown StatusTreatmentCirrhosis, Decompensated / Hepatitis B Virus (HBV)1
4Unknown StatusTreatmentHepatic Steatosis / Hepatitis B Chronic Infection1
4Unknown StatusTreatmentHepatitis B Chronic Infection8
4Unknown StatusTreatmentHepatitis B Chronic Infection / Inadequate Response / Nucleos(t)Ide Analogues Treatment1
4Unknown StatusTreatmentHepatitis, Chronic1
4Unknown StatusTreatmentHepatocellular,Carcinoma1
4Unknown StatusTreatmentViral Hepatitis B1
4WithdrawnTreatmentHepatitis B Chronic Infection2
Not AvailableActive Not RecruitingNot AvailableLiver Cirrhosis / Viral Hepatitis B1
Not AvailableActive Not RecruitingPreventionNon-Hodgkin's Lymphoma (NHL)1
Not AvailableCompletedNot AvailableEntecavir for Chronic Hepatitis B Patients1
Not AvailableCompletedNot AvailableHepatitis B Chronic Infection2
Not AvailableCompletedNot AvailableHuman Immunodeficiency Virus (HIV) Infections1
Not AvailableCompletedTreatmentChronic Heptitis B1
Not AvailableCompletedTreatmentHepatitis1
Not AvailableCompletedTreatmentHepatitis B Chronic Infection1
Not AvailableCompletedTreatmentHepatocellular,Carcinoma / Viral Hepatitis B1
Not AvailableCompletedTreatmentPrimary Liver Cancers1
Not AvailableNo Longer AvailableNot AvailableDisease, Chronic / Viral Hepatitis B1
Not AvailableNot Yet RecruitingNot AvailableHepatitis B Chronic Infection1
Not AvailableRecruitingNot AvailableLiver Cirrhosis / Viral Hepatitis B1
Not AvailableRecruitingNot AvailableLung Cancer Non-Small Cell Cancer (NSCLC) / Viral Hepatitis B1
Not AvailableRecruitingDiagnosticFibrosis, Liver / Viral Hepatitis B1
Not AvailableRecruitingTreatmentHepatitis B Chronic Infection1
Not AvailableTerminatedNot AvailableViral Hepatitis B1
Not AvailableUnknown StatusNot AvailableHepatitis B Chronic Infection / Hepatocellular,Carcinoma1
Not AvailableUnknown StatusNot AvailableViral Hepatitis B1
Not AvailableUnknown StatusTreatmentHepatitis B Chronic Infection1
Not AvailableUnknown StatusTreatmentViral Hepatitis B1

Pharmacoeconomics

Manufacturers
  • Bristol myers squibb
Packagers
  • Bristol-Myers Squibb Co.
  • E.R. Squibb and Sons LLC
Dosage forms
FormRouteStrength
SolutionOral0.05 mg/ml
SolutionOral0.05 mg/1mL
TabletOral0.5 mg
Tablet, film coatedOral0.5 mg
Tablet, film coatedOral1 mg
TabletOral0.5 mg/1
TabletOral1 mg/1
Tablet, coatedOral0.5 mg/1
Tablet, coatedOral1 mg/1
Tablet, film coatedOral0.5 mg/1
Tablet, film coatedOral1 mg/1
Tablet, film coatedOral1.0 mg/1
TabletOral1 mg
Prices
Unit descriptionCostUnit
Baraclude 0.5 mg tablet28.94USD tablet
Baraclude 1 mg tablet28.94USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2053339No2001-05-292011-10-11Canada
US5206244Yes1993-04-272015-08-21Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySlightly soluble (2.4 mg/mL at pH 7.9, 25 °C)Not Available
logP-0.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility6.59 mg/mLALOGPS
logP-0.81ALOGPS
logP-1.4ChemAxon
logS-1.6ALOGPS
pKa (Strongest Acidic)8ChemAxon
pKa (Strongest Basic)2.77ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area125.76 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity71 m3·mol-1ChemAxon
Polarizability27.31 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.873
Caco-2 permeable-0.7601
P-glycoprotein substrateSubstrate0.5802
P-glycoprotein inhibitor INon-inhibitor0.863
P-glycoprotein inhibitor IINon-inhibitor0.9185
Renal organic cation transporterNon-inhibitor0.8465
CYP450 2C9 substrateNon-substrate0.8817
CYP450 2D6 substrateNon-substrate0.8164
CYP450 3A4 substrateNon-substrate0.5346
CYP450 1A2 substrateNon-inhibitor0.7641
CYP450 2C9 inhibitorNon-inhibitor0.848
CYP450 2D6 inhibitorNon-inhibitor0.915
CYP450 2C19 inhibitorNon-inhibitor0.87
CYP450 3A4 inhibitorNon-inhibitor0.9647
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9552
Ames testNon AMES toxic0.7523
CarcinogenicityNon-carcinogens0.8026
BiodegradationNot ready biodegradable0.9669
Rat acute toxicity2.3879 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8865
hERG inhibition (predictor II)Non-inhibitor0.9062
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 nucleoside and nucleotide analogues. These are analogues of nucleosides and nucleotides. These include phosphonated nucleosides, C-glycosylated nucleoside bases, analogues where the sugar unit is a pyranose, and carbocyclic nucleosides, among others.
Kingdom
Organic compounds
Super Class
Nucleosides, nucleotides, and analogues
Class
Nucleoside and nucleotide analogues
Sub Class
Not Available
Direct Parent
Nucleoside and nucleotide analogues
Alternative Parents
Hypoxanthines / 6-oxopurines / Pyrimidones / Aminopyrimidines and derivatives / N-substituted imidazoles / Cyclopentanols / Vinylogous amides / Heteroaromatic compounds / Cyclic alcohols and derivatives / Azacyclic compounds
show 5 more
Substituents
6-oxopurine / Hypoxanthine / Purinone / Purine / Imidazopyrimidine / Aminopyrimidine / Pyrimidone / Cyclopentanol / Pyrimidine / N-substituted imidazole
show 20 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
secondary alcohol, oxopurine, primary alcohol, 2-aminopurines (CHEBI:473990)

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
Yes
Actions
Other
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Sims KA, Woodland AM: Entecavir: a new nucleoside analog for the treatment of chronic hepatitis B infection. Pharmacotherapy. 2006 Dec;26(12):1745-57. [PubMed:17125436]
  2. Walsh AW, Langley DR, Colonno RJ, Tenney DJ: Mechanistic characterization and molecular modeling of hepatitis B virus polymerase resistance to entecavir. PLoS One. 2010 Feb 12;5(2):e9195. doi: 10.1371/journal.pone.0009195. [PubMed:20169198]

Drug created on June 13, 2005 07:24 / Updated on November 17, 2018 04:48