Elbasvir

Identification

Summary

Elbasvir is an antiviral and NS5A inhibitor used to treat hepatitis C infections.

Brand Names
Zepatier
Generic Name
Elbasvir
DrugBank Accession Number
DB11574
Background

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
Thumb
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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
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

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
AbametapirThe serum concentration of Elbasvir can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Elbasvir can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Elbasvir.
AcalabrutinibThe metabolism of Elbasvir can be decreased when combined with Acalabrutinib.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Elbasvir.
AdalimumabThe metabolism of Elbasvir can be increased when combined with Adalimumab.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Elbasvir.
AfatinibThe serum concentration of Elbasvir can be increased when it is combined with Afatinib.
AlfentanilThe metabolism of Elbasvir can be decreased when combined with Alfentanil.
AlfuzosinThe metabolism of Alfuzosin can be decreased when combined with Elbasvir.
Interactions
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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

Products
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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
ZepatierElbasvir (50 mg/1) + Grazoprevir (100 mg/1)Tablet, film coatedOralMerck Sharp & Dohme Corp.2016-01-28Not applicableUS flag
ZepatierElbasvir (50 mg) + Grazoprevir (100 mg)TabletOralMerck Ltd.2016-01-25Not applicableCanada flag
ZEPATIERElbasvir (50 MG) + Grazoprevir (100 MG)Tablet, film coatedOralบริษัท เอ็มเอสดี (ประเทศไทย) จำกัด2017-06-092020-08-13Thailand flag
ZepatierElbasvir (50 mg) + Grazoprevir (100 mg)Tablet, film coatedOralMerck Sharp & Dohme B.V.2016-09-08Not applicableEU flag
ZEPATIER 50 MG/100 MG FİLM KAPLI TABLET, 28 ADETElbasvir (50 mg) + Grazoprevir (100 mg)Tablet, coatedOralMERCK SHARP DOHME İLAÇLARI LTD. ŞTİ.2020-08-14Not applicableTurkey flag
ZEPATIER� TABLETAS RECUBIERTASElbasvir (50 mg) + Grazoprevir (100 mg)Tablet, coatedOralBEND RESEARCH INC.2018-07-25Not applicableColombia flag

Categories

ATC Codes
J05AP54 — Elbasvir and grazoprevirJ05AP10 — Elbasvir
Drug Categories
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
show 7 more
Substituents
Alpha-amino acid amide / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Carbamic acid ester / Carbonic acid derivative / Carbonyl group / Carboxamide group / Heteroaromatic compound
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Hepatitis C Virus
  • SARS-CoV-2

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][C@]1(CCCN1C(=O)[C@@H](NC(=O)OC)C(C)C)C1=NC=C(N1)C1=CC2=C(C=C1)N1[C@@H](OC3=C(C=CC(=C3)C3=CN=C(N3)[C@]3([H])CCCN3C(=O)[C@@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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  5. Balasubramaniam M, Reis RS: Computational Target-Based Drug Repurposing of Elbasvir, an Antiviral Drug Predicted to Bind Multiple SARS-CoV-2 Proteins ChemRxiv. [Article]
  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]
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
PhaseStatusPurposeConditionsCount
4CompletedPreventionKidney Failure1
4CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection2
4CompletedTreatmentEnd Stage Renal Disease (ESRD) / Hepatitis C Viral Infection1
4CompletedTreatmentHemodialysis Treatment / Hepatitis C Viral Infection / Hospital Acquired Infections1
4CompletedTreatmentHepatitis C Viral Infection1
4CompletedTreatmentHepatitis C Viral Infection / Stage 3 Chronic Kidney Disease1
4CompletedTreatmentHepatitis C Viral Infection / Substance Abuse, Intravenous / Substance Use Disorders (SUD)1
4RecruitingBasic ScienceCardiovascular Disease (CVD) / Hepatitis C Viral Infection / Human Immunodeficiency Virus (HIV) Infections1
4RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection1
4RecruitingTreatmentDisorder of Transplanted Kidney / Hepatitis C Viral Infection / Renal Insufficiency,Chronic1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Tablet, coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8871759No2014-10-282031-05-04US flag
US7973040No2011-07-052029-07-24US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00457 mg/mLALOGPS
logP5.6ALOGPS
logP6.14ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)11.11ChemAxon
pKa (Strongest Basic)6.06ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area188.8 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity241.52 m3·mol-1ChemAxon
Polarizability100.15 Å3ChemAxon
Number of Rings9ChemAxon
Bioavailability0ChemAxon
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

Targets

Drugtargets
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Kind
Protein
Organism
Hepatitis C Virus
Pharmacological action
Yes
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Not Available
Gene Name
NS5A
Uniprot ID
Q5L478
Uniprot Name
Nonstructural protein 5A
Molecular Weight
48598.34 Da

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Monooxygenase activity
Specific Function
Exhibits low testosterone 6-beta-hydroxylase activity.
Gene Name
CYP3A43
Uniprot ID
Q9HB55
Uniprot Name
Cytochrome P450 3A43
Molecular Weight
57669.21 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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

Drug created on April 07, 2016 16:37 / Updated on March 04, 2021 09:26