Entecavir

Identification

Name

Entecavir

Accession Number

DB00442

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.

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 277.2792
Monoisotopic: 277.117489371
Chemical Formula: C₁₂H₁₅N₅O₃

Synonyms

Anhydrous entecavir
Entecavir
Entecavir (anhydrous)
Entecavir anhydrous
Entecavirum

External IDs

BMS-200475-01
ETV
SQ34676

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

Hepatitis B Chronic Infection

Contraindications & Blackbox Warnings

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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.

Target	Actions	Organism
ADNA	other	Humans

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]

Adverse Effects

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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

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.

Drug	Interaction
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Abametapir	The serum concentration of Entecavir can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Entecavir can be increased when combined with Abatacept.
Abiraterone	The serum concentration of Entecavir can be increased when it is combined with Abiraterone.
Acenocoumarol	The metabolism of Acenocoumarol can be decreased when combined with Entecavir.
Acetaminophen	The metabolism of Entecavir can be decreased when combined with Acetaminophen.
Acyclovir	The metabolism of Acyclovir can be decreased when combined with Entecavir.
Adalimumab	The metabolism of Entecavir can be increased when combined with Adalimumab.
Adenovirus type 7 vaccine live	The therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Entecavir.
Agomelatine	The metabolism of Agomelatine can be decreased when combined with Entecavir.
Albendazole	The metabolism of Albendazole can be decreased when combined with Entecavir.

Additional Data Available

Extended Description

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Extended description of the mechanism of action and particular properties of each drug interaction.

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Severity

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A severity rating for each drug interaction, from minor to major.

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Evidence Level

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A rating for the strength of the evidence supporting each drug interaction.

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Action

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An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions

Take on an empty stomach. Take 2 hours before or 2 hours after a meal.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Entecavir monohydrate	5968Y6H45M	209216-23-9	YXPVEXCTPGULBZ-WQYNNSOESA-N
Entecavir triphosphate	Not Available	Not Available	ZTWBIZVVFNIRSF-HAFWLYHUSA-N

Product Images

International/Other Brands

Barcavir (Incepta) / Caavirel (PMP) / Entaliv (Dr. Reddy's Laboratories) / Teviral (ACI)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
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Baraclude	Tablet, film coated	0.5 mg	Oral	Bristol Myers Squibb Pharma Eeig	2006-06-26	Not applicable
Baraclude	Tablet	0.5 mg	Oral	Bristol Myers Squibb	2006-09-12	Not applicable
Baraclude	Tablet, film coated	0.5 mg/1	Oral	E.R. Squibb & Sons, L.L.C.	2005-03-29	Not applicable
Baraclude	Solution	0.05 mg/ml	Oral	Bristol Myers Squibb Pharma Eeig	2006-06-26	Not applicable
Baraclude	Tablet, film coated	1 mg	Oral	Bristol Myers Squibb Pharma Eeig	2006-06-26	Not applicable
Baraclude	Solution	0.05 mg/1mL	Oral	E.R. Squibb & Sons, L.L.C.	2005-03-29	Not applicable
Baraclude	Tablet, film coated	1 mg	Oral	Bristol Myers Squibb Pharma Eeig	2006-06-26	Not applicable
Baraclude	Tablet, film coated	1 mg	Oral	Bristol Myers Squibb Pharma Eeig	2006-06-26	Not applicable
Baraclude	Tablet, film coated	0.5 mg	Oral	Bristol Myers Squibb Pharma Eeig	2006-06-26	Not applicable
Baraclude	Tablet, film coated	1.0 mg/1	Oral	E.R. Squibb & Sons, L.L.C.	2005-03-29	Not applicable

Additional Data Available

Application Number

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A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

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A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
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Accel-entecavir	Tablet		Oral	Accel Pharma Inc	2020-03-11	Not applicable
Apo-entecavir	Tablet		Oral	Apotex Corporation	2013-01-18	Not applicable
Auro-entecavir	Tablet		Oral	Auro Pharma Inc	2015-12-01	Not applicable
Entecavir	Tablet, film coated	0.5 mg/1	Oral	Par Pharmaceutical	2014-08-18	2017-08-31
Entecavir	Tablet, film coated	0.5 mg/1	Oral	AvKARE	2020-11-02	Not applicable
Entecavir	Tablet	0.5 mg/1	Oral	BrightGene Bio-Medical Technology Co., Ltd.	2019-03-08	Not applicable
Entecavir	Tablet, film coated	1 mg/1	Oral	Amneal Pharmaceuticals LLC	2014-11-28	Not applicable
Entecavir	Tablet, film coated	0.5 mg/1	Oral	Accord Healthcare Inc.	2018-02-21	Not applicable
Entecavir	Tablet	1 mg/1	Oral	Breckenridge Pharmaceutical, Inc.	2018-03-16	Not applicable
Entecavir	Tablet	0.5 mg/1	Oral	American Health Packaging	2016-07-26	Not applicable

Additional Data Available

Application Number

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A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

Available for Purchase

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Chemical Identifiers

UNII: NNU2O4609D
CAS number: 142217-69-4
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)[[email protected]]1C[[email protected]](O)[[email protected]@H](CO)C1=C

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
RxNav: 1546027
ChEBI: 473990
ChEMBL: CHEMBL713
ZINC: ZINC000003802690
Therapeutic Targets Database: DAP000697
PharmGKB: PA164784025
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Entecavir

AHFS Codes

08:18.32 — Nucleosides and Nucleotides

FDA label

Download (628 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Prevention	Exposure to Hepatitis B Virus / Reactivation of hepatitis B virus infection / Rheumatoid Arthritis	1
4	Active Not Recruiting	Treatment	Hepatitis B Chronic Infection	1
4	Active Not Recruiting	Treatment	Liver Cirrhosis / Viral Hepatitis B	1
4	Active Not Recruiting	Treatment	Viral Hepatitis B	1
4	Completed	Prevention	Non-Hodgkin's Lymphoma (NHL) / Viral Hepatitis B	1
4	Completed	Treatment	Chronic Viral Hepatitis B Without Delta-agent	2
4	Completed	Treatment	Fibrosis, Liver	1
4	Completed	Treatment	HBeAg-Positive Chronic Hepatitis B	1
4	Completed	Treatment	Hepatitis B Chronic Infection	18
4	Completed	Treatment	Hepatitis B Infection	1

Pharmacoeconomics

Manufacturers

Bristol myers squibb

Packagers

Bristol-Myers Squibb Co.
E.R. Squibb and Sons LLC

Dosage Forms

Form	Route	Strength
Tablet	Oral
Solution	Oral	0.05 mg/1mL
Solution	Oral	0.05 mg/ml
Solution	Oral	50 mcg/1mL
Tablet, coated	Oral	500 mcg
Tablet, film coated	Oral	0.5 mg
Tablet, film coated	Oral	1 mg
Tablet, film coated	Oral	1.0 MG
Tablet, coated	Oral	0.5 mg
Tablet, coated	Oral	1 mg
Tablet	Oral	0.5 mg
Tablet	Oral	1 mg
Tablet	Oral	0.5 mg/1
Tablet	Oral	1 mg/1
Tablet, coated	Oral	0.5 mg/1
Tablet, coated	Oral	1 mg/1
Tablet, film coated	Oral	0.5 mg/1
Tablet, film coated	Oral	1 mg/1
Tablet, film coated	Oral	1.0 mg/1
Tablet, film coated	Oral

Prices

Unit description	Cost	Unit
Baraclude 0.5 mg tablet	28.94USD	tablet
Baraclude 1 mg tablet	28.94USD	tablet

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
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CA2053339	No	2001-05-29	2011-10-11
US5206244	Yes	1993-04-27	2015-08-21

Additional Data Available

Filed On

Available for Purchase

The date on which a patent was filed with the relevant government.

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Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Slightly soluble (2.4 mg/mL at pH 7.9, 25 °C)	Not Available
logP	-0.8	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	6.59 mg/mL	ALOGPS
logP	-0.81	ALOGPS
logP	-1.4	ChemAxon
logS	-1.6	ALOGPS
pKa (Strongest Acidic)	8	ChemAxon
pKa (Strongest Basic)	2.77	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	7	ChemAxon
Hydrogen Donor Count	4	ChemAxon
Polar Surface Area	125.76 Å²	ChemAxon
Rotatable Bond Count	2	ChemAxon
Refractivity	71 m³·mol^-1	ChemAxon
Polarizability	27.31 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	1.0
Blood Brain Barrier	+	0.873
Caco-2 permeable	-	0.7601
P-glycoprotein substrate	Substrate	0.5802
P-glycoprotein inhibitor I	Non-inhibitor	0.863
P-glycoprotein inhibitor II	Non-inhibitor	0.9185
Renal organic cation transporter	Non-inhibitor	0.8465
CYP450 2C9 substrate	Non-substrate	0.8817
CYP450 2D6 substrate	Non-substrate	0.8164
CYP450 3A4 substrate	Non-substrate	0.5346
CYP450 1A2 substrate	Non-inhibitor	0.7641
CYP450 2C9 inhibitor	Non-inhibitor	0.848
CYP450 2D6 inhibitor	Non-inhibitor	0.915
CYP450 2C19 inhibitor	Non-inhibitor	0.87
CYP450 3A4 inhibitor	Non-inhibitor	0.9647
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9552
Ames test	Non AMES toxic	0.7523
Carcinogenicity	Non-carcinogens	0.8026
Biodegradation	Not ready biodegradable	0.9669
Rat acute toxicity	2.3879 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.8865
hERG inhibition (predictor II)	Non-inhibitor	0.9062

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

Details1. DNA

Kind

Nucleotide

Organism

Humans

Pharmacological action

Yes

Actions

Other

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

References

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]
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]