Identification

Name
Elbasvir
Accession Number
DB11574
Type
Small Molecule
Groups
Approved
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, and affecting 72% of all chronic HCV patients [5]. 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 for develoment of resistance to NS5A inhibitors is lower than that of NS5B inhibitors, another class of DAAs [3]. Subtitutions at amino acid positions 28, 30, 31, or 93 are known to confer resistance to Elbasvir [Label]. Despite this disadvantage Elbasvir is still effective against HCV particularly when paired with Grazoprevir.

In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend Elbasvir as first line therapy in combination with Grazoprevir for genotypes 1a, 1b, and 4 of Hepatitis C [3]. Elbasvir and Grazoprevir are used with or without Ribavirin with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection is 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].

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 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 [Label]. When combined together, Elbasvir and Grazoprevir as the combination product Zepatier 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 [5]. It can be used in patients with compensated cirrhosis, human immunodeficiency virus co-infection, or severe kidney disease.

Structure
Thumb
Synonyms
Not Available
External IDs
MK 8742 / MK-8742 / MK8742
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
ZepatierElbasvir (50 mg) + Grazoprevir (100 mg)Tablet, film coatedOralMerck Sharp & Dohme B.V.2016-07-22Not applicableEu
ZepatierElbasvir (50 mg/1) + Grazoprevir (100 mg/1)Tablet, film coatedOralMerck Sharp & Dohme Limited2016-01-28Not applicableUs
ZepatierElbasvir (50 mg) + Grazoprevir (100 mg)TabletOralMerck Ltd.2016-01-25Not applicableCanada
Categories
UNII
632L571YDK
CAS number
1370468-36-2
Weight
Average: 882.035
Monoisotopic: 881.422445147
Chemical Formula
C49H55N9O7
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-{4-[(9S)-5-{2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-4-yl}-9-phenyl-8-oxa-10-azatetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadeca-1(17),2(7),3,5,11(16),12,14-heptaen-14-yl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate
SMILES
COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC(=CN1)C1=CC2=C(C=C1)N1[C@@H](OC3=C(C=CC(=C3)C3=CNC(=N3)[C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)C)C1=C2)C1=CC=CC=C1

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 [Label].

Associated Conditions
Pharmacodynamics

Elbasvir is classified as a direct-acting antiviral (DAA) and prevents viral replication in HCV genotypes 1a, 1b, and 4 [Label].

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].

TargetActionsOrganism
ANonstructural Protein 5A (NS5A)
inhibitor
Hepatitis C Virus (HCV)
Absorption

Elbasvir reaches peak plasma concentration 3-6 hours after administration [Label]. Elbasvir has an absolute bioavailability of 32%. When taken with food the peak concentration of Elbasvir increases 1.5 fold but this increase in exposure has not been deemed clinically relevant.

Volume of distribution

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

Protein binding

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

Metabolism

Elbasvir is partially eliminated by oxidative metabolism meditated by CYP3A [Label]. No circulating metabolites of 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%) [Label].

Half life

The geometric mean apparent terminal half-life for Grazoprevir is 24 hours in HCV-infected subjects [Label].

Clearance

The clearance of Elbasvir has not been determined [Label].

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 [Label].

Affected organisms
  • Hepatitis C Virus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenThe serum concentration of Elbasvir can be increased when it is combined with Acetaminophen.
Acetyl sulfisoxazoleThe metabolism of Elbasvir can be decreased when combined with Acetyl sulfisoxazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Elbasvir.
AlfuzosinThe metabolism of Alfuzosin can be decreased when combined with Elbasvir.
AmcinonideThe metabolism of Amcinonide can be decreased when combined with Elbasvir.
AmiodaroneThe serum concentration of Elbasvir can be increased when it is combined with Amiodarone.
AmitriptylineThe metabolism of Amitriptyline can be decreased when combined with Elbasvir.
AmlodipineThe serum concentration of Elbasvir can be increased when it is combined with Amlodipine.
AmsacrineThe serum concentration of Elbasvir can be increased when it is combined with Amsacrine.
ApalutamideThe serum concentration of Elbasvir can be decreased when it is combined with Apalutamide.
Food Interactions
Not Available

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. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance. http://hcvguidelines.org. Accessed June 12, 2017. [Link]
External Links
KEGG Drug
D10625
PubChem Compound
71661251
PubChem Substance
347827988
ChemSpider
30843797
ChEBI
132967
ChEMBL
CHEMBL3039514
PharmGKB
PA166163436
RxList
RxList Drug Page
Wikipedia
Elbasvir
FDA label
Download (441 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentHepatitis C Viral Infection / Transplant, Kidney1
1CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Impaired Renal Function1
1CompletedTreatmentHepatic Insufficiency1
1CompletedTreatmentHepatitis, Viral, Human1
1, 2RecruitingTreatmentEnd Stage Renal Disease (ESRD)1
1, 2RecruitingTreatmentHeart Failure, Unspecified1
2CompletedTreatmentHepatitis C Viral Infection7
2CompletedTreatmentHepatitis C Virus (HCV)1
2RecruitingTreatmentHepatitis C, Acute / Human Immunodeficiency Virus (HIV)1
2, 3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection1
2, 3CompletedTreatmentHepatitis C Viral Infection1
2, 3CompletedTreatmentHepatitis C Virus (HCV)1
3Active Not RecruitingTreatmentHepatitis C Viral Infection / Hepatitis C, Acute / Human Immunodeficiency Virus (HIV)1
3Active Not RecruitingTreatmentHepatitis C Viral Infection / Human Immunodeficiency Virus (HIV)1
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection1
3CompletedTreatmentHepatitis C Infection1
3CompletedTreatmentHepatitis C Viral Infection2
3Not Yet RecruitingTreatmentChronic HCV Hepatitis1
3Not Yet RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection1
3Not Yet RecruitingTreatmentChronic hepatitis C genotype 1b / Cirrhoses, Liver / Fibrosis, Liver / Metabolic Syndromes1
3Not Yet RecruitingTreatmentCompensated liver disease / Hepatitis C Viral Infection1
3RecruitingTreatmentChronic HCV Infection1
3RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection1
3WithdrawnTreatmentHepatitis C Viral Infection1
3WithdrawnTreatmentHepatitis C Viral Infection / Transplantation, Liver1
4Active Not RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection1
4CompletedTreatmentEnd-Stage Renal Disease (ESRD) / Hepatitis C Viral Infection1
4Enrolling by InvitationTreatmentHepatitis C Viral Infection / Substance Abuse, Intravenous / Substance Use Disorder (SUD)1
4Not Yet RecruitingPreventionCardiac Transplant Disorder / Hepatitis C Viral Infection1
4Not Yet RecruitingPreventionChronic Renal Failure (CRF) / Hepatitis C Viral Infection1
4Not Yet RecruitingTreatmentHepatitis C Viral Infection1
4Not Yet RecruitingTreatmentHemodialysis-dependent patients / Hepatitis C Viral Infection / Hospital Acquired Infections1
4Not Yet RecruitingTreatmentHepatitis C Virus Infection, Response to Therapy of1
4Not Yet RecruitingTreatmentTo Assess the Efficacy of Grazoprevir 100mg and Elbasvir 50mg by Determining the Proportion of Sustained Virological Response 12 Weeks After the End of Therapy1
4RecruitingPreventionRenal Failure1
4RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection1
4RecruitingTreatmentDisorder of Transplanted Kidney / Hepatitis C Viral Infection / Renal Insufficiency,Chronic1
4RecruitingTreatmentHepatitis C Viral Infection3
4RecruitingTreatmentHepatitis C Viral Infection / Human Immunodeficiency Virus (HIV)1
4WithdrawnOtherHepatitis C Viral Infection1
4WithdrawnTreatmentHCV1
4WithdrawnTreatmentHepatitis C Viral Infection1
Not AvailableCompletedNot AvailableChronic Kidney Disease (CKD) / Hepatitis C Viral Infection1
Not AvailableNot Yet RecruitingNot AvailableCryoglobulinaemic Glomerulonephritis / Hepatitis C Viral Infection1
Not AvailableNot Yet RecruitingTreatmentHCV, HCC1
Not AvailableRecruitingNot AvailableChronic Hepatitis C Virus (HCV) Infection1
Not AvailableRecruitingNot AvailableChronic Hepatitis C Virus (HCV) Infection / Human Immunodeficiency Virus (HIV)1
Not AvailableRecruitingNot AvailableHepatitis C Viral Infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8871759No2011-05-042031-05-04Us
US7973040No2009-07-242029-07-24Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0044 mg/mLALOGPS
logP6.17ALOGPS
logP7.07ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)12.42ChemAxon
pKa (Strongest Basic)5.39ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area188.8 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity241.02 m3·mol-1ChemAxon
Polarizability98.71 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

Taxonomy

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
Valine or derivatives / Alpha-amino acid amide / Indole / Indole or derivatives / N-acylpyrrolidine / Monocyclic benzene moiety / Benzenoid / Methylcarbamate / Azole / Imidazole
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

1. Nonstructural Protein 5A (NS5A)
Kind
Protein
Organism
Hepatitis C Virus (HCV)
Pharmacological action
Yes
Actions
Inhibitor

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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
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

Drug created on April 07, 2016 10:37 / Updated on September 21, 2018 00:19