Elbasvir

Identification

Name

Elbasvir

Accession Number

DB11574

Description

Elbasvir is a direct-acting antiviral medication used as part of combination therapy to treat chronic hepatitis C, an infectious liver disease caused by infection with hepatitis C virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, affecting 72% of all chronic HCV patients.⁶ Treatment options for chronic hepatitis C have advanced significantly since 2011, with the development of direct-acting antivirals (DAAs) such as elbasvir. Elbasvir is an inhibitor of NS5A, a protein essential for viral replication and virion assembly.^Synthesis The barrier to the development of resistance to NS5A inhibitors is lower than that of NS5B inhibitors, another class of DAAs.³ Substitutions at amino acid positions 28, 30, 31, or 93 are known to confer resistance to elbasvir.⁷ Despite this disadvantage elbasvir is still effective against HCV, particularly when paired with grazoprevir.

Elbasvir is available as a fixed-dose combination product with grazoprevir (tradename: Zepatier) used for the treatment of chronic hepatitis C. Approved in January 2016 by the FDA, Zepatier is indicated for the treatment of HCV genotypes 1 and 4 with or without ribavirin depending on the presence of resistance-associated amino acid substitutions in the NS5A protein and previous treatment failure with ribavirin, peginterferon alfa-2a, peginterferon alfa-2b, or other NS3/4A inhibitors like boceprevir, simeprevir, or telaprevir.⁷ Elbasvir and grazoprevir are used with or without ribavirin with the intent to cure, or achieve a sustained virologic response (SVR), and have been shown to achieve a SVR between 94% and 97% for genotype 1 and 97% and 100% for genotype 4 after 12 weeks of treatment.⁶. SVR and eradication of HCV infection are associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of hepatocellular carcinoma, and reduced all-cause mortality.⁴

In a computational target-based drug repurposing investigation published in April 2020, elbasvir was predicted to bind stably and preferentially to three proteins necessary for viral replication of SARS-CoV-2, the human coronavirus responsible for the COVID-19 pandemic.⁵ While these results are suggestive of antiviral efficacy, follow-up clinical trials are required to validate elbasvir as a potential therapy against SARS-CoV-2.

Type

Small Molecule

Groups

Approved

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Elbasvir (DB11574)

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Weight

Average: 882.035
Monoisotopic: 881.422445147

Chemical Formula

C₄₉H₅₅N₉O₇

Synonyms

• Elbasvir

External IDs

• MK 8742
• MK-8742
• MK8742

Pharmacology

Indication

Elbasvir, when used in combination with grazoprevir as the combination product Zepatier, is indicated for use with or without ribavirin for the treatment of chronic HCV genotypes 1 or 4 infection in adults.⁷

Associated Conditions

• Chronic Hepatitis C Genotype 1
• Chronic hepatitis C genotype 1a
• Chronic hepatitis C genotype 1b
• Chronic hepatitis C genotype 3
• Chronic hepatitis C genotype 4

Contraindications & Blackbox Warnings

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Pharmacodynamics

Elbasvir is classified as a direct-acting antiviral (DAA) and prevents viral replication in HCV genotypes 1a, 1b, and 4.⁷

Mechanism of action

Elbasvir is an inhibitor of the HCV non-structural protein 5A. While the precise role of this protein is unknown, it is essential to viral replication and virion assembly.^Synthesis Potential modes of action of NS5A inhibitors like elbasvir include blocking signaling interactions, redistribution of NS5A from the endoplasmic reticulum to the surface of lipid droplets, and modification of the HCV replication complex.³

Computational target-based in silico research suggests that elbasvir may carry activity at several proteins required for replication of SARS-CoV-2 - namely RNA-dependent RNA polymerase, helicase, and papain-like proteinase - although specific activity has yet to be affirmed by follow-up clinical studies.⁵

Target	Actions	Organism
ANonstructural protein 5A	inhibitor	Hepatitis C Virus

Absorption

Elbasvir reaches peak plasma concentration 3-6 hours after administration⁷ and has an absolute bioavailability of 32%. When co-administered with food, the peak concentration of elbasvir increases 1.5-fold, but this increase in exposure is not likely to be clinically relevant.

Volume of distribution

Elbasvir has an estimated apparent volume of distribution of 680 liters.⁷ It is thought to distribute into most tissues including the liver.

Protein binding

Elbasvir is more than 99.9% bound to plasma proteins.⁷ It binds both human serum albumin and α1-acid glycoprotein.

Metabolism

Elbasvir is partially eliminated by oxidative metabolism meditated by CYP3A.⁷ No circulating metabolites of elbasvir have been detected in human plasma.

Route of elimination

Elbasvir is mainly eliminated in the feces (90%) with very little eliminated in the urine (<1%).⁷

Half-life

The geometric mean apparent terminal half-life for elbasvir is 24 hours in HCV-infected subjects.⁷

Clearance

The clearance of elbasvir has not been determined.⁷

Adverse Effects

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Toxicity

The most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache, and nausea.⁷

Affected organisms

• Hepatitis C Virus
• SARS-CoV-2

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Elbasvir can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Elbasvir can be increased when combined with Abatacept.
Abiraterone	The metabolism of Abiraterone can be decreased when combined with Elbasvir.
Acalabrutinib	The metabolism of Elbasvir can be decreased when combined with Acalabrutinib.
Acenocoumarol	The serum concentration of Acenocoumarol can be increased when it is combined with Elbasvir.
Adalimumab	The metabolism of Elbasvir 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 Elbasvir.
Afatinib	The serum concentration of Elbasvir can be increased when it is combined with Afatinib.
Albendazole	The metabolism of Albendazole can be decreased when combined with Elbasvir.
Alectinib	The metabolism of Alectinib can be decreased when combined with Elbasvir.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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Severity
Severity
A severity rating for each drug interaction, from minor to major.
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Evidence Level
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
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Action
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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Food Interactions

• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of elbasvir. Co-administration of Elbasvir with St. John's Wort is contraindicated.
• Exercise caution with grapefruit products. Grapefruit inhibits CYP3A, which may increase the serum levels of elbasvir, a CYP3A substrate.
• Take at the same time every day.
• Take with or without food.

Products

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Zepatier	Elbasvir (50 mg/1) + Grazoprevir (100 mg/1)	Tablet, film coated	Oral	Merck Sharp & Dohme Corp.	2016-01-28	Not applicable
Zepatier	Elbasvir (50 mg) + Grazoprevir (100 mg)	Tablet, film coated	Oral	Merck Sharp & Dohme B.V.	2016-07-22	Not applicable
Zepatier	Elbasvir (50 mg) + Grazoprevir (100 mg)	Tablet	Oral	Merck Ltd.	2016-01-25	Not applicable

Categories

ATC Codes

J05AP54 — Elbasvir and grazoprevir

• J05AP — Antivirals for treatment of HCV infections
• J05A — DIRECT ACTING ANTIVIRALS
• J05 — ANTIVIRALS FOR SYSTEMIC USE
• J — ANTIINFECTIVES FOR SYSTEMIC USE

J05AP10 — Elbasvir

• J05AP — Antivirals for treatment of HCV infections
• J05A — DIRECT ACTING ANTIVIRALS
• J05 — ANTIVIRALS FOR SYSTEMIC USE
• J — ANTIINFECTIVES FOR SYSTEMIC USE

Drug Categories

• Antiinfectives for Systemic Use
• Antiviral Agents
• Antivirals for Systemic Use
• Antivirals for treatment of HCV infections
• Breast Cancer Resistance Protein Inhibitors
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A5 Inhibitors
• Cytochrome P-450 CYP3A5 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A5 Substrates
• Cytochrome P-450 CYP3A7 Inhibitors
• Cytochrome P-450 CYP3A7 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A7 Substrates
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Direct Acting Antivirals
• Experimental Unapproved Treatments for COVID-19
• Hepatitis C Virus NS5A Inhibitor
• Heterocyclic Compounds, Fused-Ring
• P-glycoprotein inhibitors
• P-glycoprotein substrates

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as valine and derivatives. These are compounds containing valine or a derivative thereof resulting from reaction of valine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.

Kingdom

Organic compounds

Super Class

Organic acids and derivatives

Class

Carboxylic acids and derivatives

Sub Class

Amino acids, peptides, and analogues

Direct Parent

Valine and derivatives

Alternative Parents

Alpha amino acid amides / Indoles / N-acylpyrrolidines / Benzene and substituted derivatives / Tertiary carboxylic acid amides / Pyrroles / Heteroaromatic compounds / Imidazoles / Methylcarbamates / Organic carbonic acids and derivatives / Oxacyclic compounds / Azacyclic compounds / Carbonyl compounds / Hydrocarbon derivatives / Organopnictogen compounds / Organic oxides / Organonitrogen compounds

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Substituents

Alpha-amino acid amide / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Carbamic acid ester / Carbonic acid derivative / Carbonyl group / Carboxamide group / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / Indole / Indole or derivatives / Methylcarbamate / Monocyclic benzene moiety / N-acylpyrrolidine / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Oxacycle / Pyrrole / Pyrrolidine / Tertiary carboxylic acid amide / Valine or derivatives

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Chemical Identifiers

UNII

632L571YDK

CAS number

1370468-36-2

InChI Key

BVAZQCUMNICBAQ-PZHYSIFUSA-N

InChI

InChI=1S/C49H55N9O7/c1-27(2)41(54-48(61)63-5)45(59)56-20-10-14-37(56)43-50-25-34(52-43)30-17-19-36-32(22-30)23-39-33-18-16-31(24-40(33)65-47(58(36)39)29-12-8-7-9-13-29)35-26-51-44(53-35)38-15-11-21-57(38)46(60)42(28(3)4)55-49(62)64-6/h7-9,12-13,16-19,22-28,37-38,41-42,47H,10-11,14-15,20-21H2,1-6H3,(H,50,52)(H,51,53)(H,54,61)(H,55,62)/t37-,38-,41-,42-,47-/m0/s1

IUPAC Name

methyl N-[(2S)-1-[(2S)-2-{5-[(9S)-14-{2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl}-9-phenyl-8-oxa-10-azatetracyclo[8.7.0.0^{2,7}.0^{11,16}]heptadeca-1(17),2(7),3,5,11(16),12,14-heptaen-5-yl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate

SMILES

[H][[email protected]]1(CCCN1C(=O)[[email protected]@H](NC(=O)OC)C(C)C)C1=NC=C(N1)C1=CC2=C(C=C1)N1[[email protected]@H](OC3=C(C=CC(=C3)C3=CN=C(N3)[[email protected]]3([H])CCCN3C(=O)[[email protected]@H](NC(=O)OC)C(C)C)C1=C2)C1=CC=CC=C1

References

Synthesis Reference

Coburn CA, Meinke PT, Chang W, Fandozzi CM, Graham DJ, Hu B, Huang Q, Kargman S, Kozlowski J, Liu R, McCauley JA, Nomeir AA, Soll RM, Vacca JP, Wang D, Wu H, Zhong B, Olsen DB, Ludmerer SW: Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity. ChemMedChem. 2013 Dec;8(12):1930-40. doi: 10.1002/cmdc.201300343. Epub 2013 Oct 14.

General References

1. Bell AM, Wagner JL, Barber KE, Stover KR: Elbasvir/Grazoprevir: A Review of the Latest Agent in the Fight against Hepatitis C. Int J Hepatol. 2016;2016:3852126. doi: 10.1155/2016/3852126. Epub 2016 Jun 15. [PubMed:27403342]
2. Coburn CA, Meinke PT, Chang W, Fandozzi CM, Graham DJ, Hu B, Huang Q, Kargman S, Kozlowski J, Liu R, McCauley JA, Nomeir AA, Soll RM, Vacca JP, Wang D, Wu H, Zhong B, Olsen DB, Ludmerer SW: Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity. ChemMedChem. 2013 Dec;8(12):1930-40. doi: 10.1002/cmdc.201300343. Epub 2013 Oct 14. [PubMed:24127258]
3. Bagaglio S, Uberti-Foppa C, Morsica G: Resistance Mechanisms in Hepatitis C Virus: implications for Direct-Acting Antiviral Use. Drugs. 2017 May 12. doi: 10.1007/s40265-017-0753-x. [PubMed:28497432]
4. Myers RP, Shah H, Burak KW, Cooper C, Feld JJ: An update on the management of chronic hepatitis C: 2015 Consensus guidelines from the Canadian Association for the Study of the Liver. Can J Gastroenterol Hepatol. 2015 Jan-Feb;29(1):19-34. Epub 2015 Jan 13. [PubMed:25585348]
5. Balasubramaniam M, Reis RS: Computational Target-Based Drug Repurposing of Elbasvir, an Antiviral Drug Predicted to Bind Multiple SARS-CoV-2 Proteins ChemRxiv.
6. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance. http://hcvguidelines.org. Accessed June 12, 2017. [Link]
7. Zepatier FDA label [Link]

External Links

KEGG Drug

D10625

PubChem Compound

71661251

PubChem Substance

347827988

ChemSpider

30843797

RxNav

1734628

ChEBI

132967

ChEMBL

CHEMBL3039514

ZINC

ZINC000150588351

PharmGKB

PA166163436

RxList

RxList Drug Page

Wikipedia

Elbasvir

FDA label

Download (441 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Chronic Hepatitis C Virus (HCV) Infection	1
4	Completed	Prevention	Renal Failure	1
4	Completed	Treatment	Chronic Hepatitis C Virus (HCV) Infection	1
4	Completed	Treatment	Chronic Kidney Disease stage3 / Hepatitis C Viral Infection	1
4	Completed	Treatment	End Stage Renal Disease (ESRD) / Hepatitis C Viral Infection	1
4	Completed	Treatment	Hemodialysis Treatment / Hepatitis C Viral Infection / Hospital Acquired Infections	1
4	Completed	Treatment	Hepatitis C Viral Infection	1
4	Completed	Treatment	Hepatitis C Viral Infection / Substance Abuse, Intravenous / Substance Use Disorders (SUD)	1
4	Recruiting	Basic Science	Cardiovascular Heart Disease / Hepatitis C Viral Infection / Human Immunodeficiency Virus (HIV) Infections	1
4	Recruiting	Treatment	Chronic Hepatitis C Virus (HCV) Infection	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral
Tablet, film coated	Oral
Tablet, film coated	Oral	50 MG
Tablet, coated	Oral	50 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
Unlock Additional Data
US8871759	No	2014-10-28	2031-05-04
US7973040	No	2011-07-05	2029-07-24

Additional Data Available

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

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00457 mg/mL	ALOGPS
logP	5.6	ALOGPS
logP	6.14	ChemAxon
logS	-5.3	ALOGPS
pKa (Strongest Acidic)	11.11	ChemAxon
pKa (Strongest Basic)	6.06	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	7	ChemAxon
Hydrogen Donor Count	4	ChemAxon
Polar Surface Area	188.8 Å2	ChemAxon
Rotatable Bond Count	13	ChemAxon
Refractivity	241.52 m3·mol-1	ChemAxon
Polarizability	100.15 Å3	ChemAxon
Number of Rings	9	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
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

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Drug created on April 07, 2016 10:37 / Updated on June 12, 2020 11:42