Glecaprevir

Identification

Summary

Glecaprevir is a Hepatitis C NS3/4A protease inhibitor used to treat Hepatitis C.

Brand Names

Maviret, Mavyret

Generic Name

Glecaprevir

DrugBank Accession Number

DB13879

Background

Glecaprevir is a direct acting antiviral agent and Hepatitis C virus (HCV) NS3/4A protease inhibitor that targets the the viral RNA replication. In combination with Pibrentasvir, glecaprevir is a useful therapy for patients who experienced therapeutic failure from other NS3/4A protease inhibitors. It demonstrates a high genetic barrier against resistance mutations of the virus. In cell cultures, the emergence of amino acid substitutions at NS3 resistance-associated positions A156 or D/Q168 in HCV genotype 1a, 2a or 3a replicons led to reduced susceptibility to glecaprevir ^Label. The combinations of amino acid substitutions at NS3 position Y65H and D/Q168 also results in greater reductions in glecaprevir susceptibility, and NS3 Q80R in genotype 3a patients also leads to glecaprevir resistance ^Label.

Glecaprevir is available as an oral combination therapy with Pibrentasvir under the brand name Mavyret. This fixed-dose combination therapy was FDA-approved in August 2017 to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis, including patients with moderate to severe kidney disease and those who are on dialysis ². Mavyret is also indicated for HCV genotype 1-infected patients who have been previously treated with regimens either containing an NS5A inhibitor or an NS3/4A protease inhibitor, but not both ². Hepatitis C viral infection often leads to decreased liver function and subsequent liver failure, causing a significantly negative impact on the patients' quality of life. The ultimate goal of the combination treatment is to achieve sustained virologic response (SVR) and cure the patients from the infection. In clinical trials, this combination therapy achieved SVR12 rate, or undetectable Hepatitis C for twelve or more weeks after the end of treatment, of ≥93% across genotypes 1a, 2a, 3a, 4, 5 and 6 ^Label.

Type

Small Molecule

Groups

Approved, Investigational

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Glecaprevir (DB13879)

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Weight

Average: 838.87
Monoisotopic: 838.298310911

Chemical Formula

C₃₈H₄₆F₄N₆O₉S

Synonyms

• Glécaprévir
• Glecaprevir
• Glecaprevirum

External IDs

• A-1282576
• A-1282576.0
• A-12825760
• ABT 493
• ABT-493

Pharmacology

Indication

Indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A). MAVYRET is also indicated for the treatment of adult patients with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor (PI), but not both ^Label.

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Associated Conditions

• Chronic Hepatitis C - Genotype 3
• Chronic Hepatitis C Genotype 1
• Chronic Hepatitis C Virus (HCV) Infection
• Chronic hepatitis C genotype 2
• Chronic hepatitis C genotype 5
• Genotype 4 Chronic Hepatitis C
• Genotype 6 chronic hepatitis C infection

Contraindications & Blackbox Warnings

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Pharmacodynamics

In a biochemical assay studying clinical isolates of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a, glecaprevir displayed IC50 values ranging from 3.5 to 11.3 nM that resulted in inhibition of the proteolytic activity of recombinant NS3/4A enzymes. In HCV replicon assays, glecaprevir had median EC50 values of 0.08-4.6 nM against laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, and 6a ^Label. In a QT study, glecaprevir is not shown to prolong the QTc interval.

Mechanism of action

Glecaprevir is an inhibitor of the HCV NS3/4A protease, which is a viral enzyme necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins ^Label. These multifunctional proteins, including NS3, are essential for viral replication. The N-terminal of NS3 protein confers serine protease activity, whileThe C-terminus of NS3 encodes a DExH/D-box RNA helicase which hydyolyzes NTP as an energy source to unwind double-stranded RNA in a 3′ to 5′ direction during replication of viral genomic RNA ¹. NS4A is a cofactor for NS3 that directs the localization of NS3 and modulates its enzymatic activities ¹. Glecaprevir disrupts the intracellular processes of the viral life cycle through inhibiting the NS3/4A protease activity of cleaving downstream junctions of HCV polypeptide and proteolytic processing of mature structural proteins ¹.

Target	Actions	Organism
ANS3 protease	inhibitor	Hepatitis C Virus

Absorption

In healthy subjects, the time it takes to reach the peak plasma concentration (Tmax) is approximately 5 hours. The mean peak plasma concentration (Cmax) is 597ng/mL in non-cirrhotic HCV-infected subjects. Relative to fasting conditions, the consumption of meals increases the absorption of glecaprevir by 83-163% ^Label.

Volume of distribution

Not Available

Protein binding

Pibrentasvir is 97.5% bound to human plasma proteins. The Blood-to-plasma ratio is approximately 0.57 ^Label.

Metabolism

Glecaprevir undergoes limited secondary metabolism in vitro, predominantly by CYP3A ^Label.

Route of elimination

The predominant route of elimination of the drug is biliary-fecal, where 92.1% of administered drug is excreted in feces and 0.7% of the drug is excreted in the urine ^Label.

Half-life

The elimination half life (t1/2) is approximately 6 hours ^Label.

Clearance

Not Available

Adverse Effects

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Toxicity

Glecaprevir is not shown to be genotoxic according to in vitro or in vivo studies. It also shows to have no effect on mating, female or male fertility, or early embryonic development in rodent studies. Carcinogenicity studies with glecaprevir have not been conducted ^Label.

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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Abacavir	The metabolism of Abacavir can be decreased when combined with Glecaprevir.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Glecaprevir.
Abrocitinib	The serum concentration of Glecaprevir can be increased when it is combined with Abrocitinib.
Acalabrutinib	The metabolism of Acalabrutinib can be decreased when combined with Glecaprevir.
Acenocoumarol	The metabolism of Acenocoumarol can be decreased when combined with Glecaprevir.
Acetaminophen	The metabolism of Acetaminophen can be decreased when combined with Glecaprevir.
Acetylcysteine	The excretion of Glecaprevir can be decreased when combined with Acetylcysteine.
Adagrasib	The serum concentration of Glecaprevir can be increased when it is combined with Adagrasib.
Adenovirus type 7 vaccine live	The therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Glecaprevir.
Afatinib	The serum concentration of Afatinib can be increased when it is combined with Glecaprevir.

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Food Interactions

• Avoid St. John's Wort. Co-administration may lead to decreased serum concentrations of glecaprevir.
• Take with food.

Products

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Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Maviret	Glecaprevir (100 mg) + Pibrentasvir (40 mg)	Tablet	Oral	Abbvie	2017-09-13	Not applicable
Maviret	Glecaprevir (100 mg) + Pibrentasvir (40 mg)	Tablet, film coated	Oral	Abb Vie Deutschland Gmb H Co. Kg	2020-12-16	Not applicable
Maviret	Glecaprevir (50 mg / sachet) + Pibrentasvir (20 mg / sachet)	Granule	Oral	Abbvie	2022-04-22	Not applicable
MAVIRET (GLECAPREVIR 100MG/ PIBRENTASVIR 40MG) FILM COATED TABLETS	Glecaprevir (100 mg) + Pibrentasvir (40 mg)	Tablet, film coated	Oral	ABBVIE SDN BHD	2020-09-08	Not applicable
MAVİRET 100 MG/40 MG FİLM KAPLI TABLET, 84 ADET	Glecaprevir (100 mg) + Pibrentasvir (40 mg)	Tablet, coated	Oral	ABBVİE TIBBİ İLAÇLAR SAN. VE TİC. LTD. ŞTİ.	2020-08-14	Not applicable
MAVIRET FILM-COATED TABLET 100MG/40MG	Glecaprevir (100.0 mg) + Pibrentasvir (40.0 mg)	Tablet, film coated	Oral	ABBVIE PTE. LTD.	2018-12-26	Not applicable
Mavyret	Glecaprevir (100 mg/1) + Pibrentasvir (40 mg/1)	Tablet, film coated	Oral	AbbVie Inc.	2017-08-03	Not applicable
Mavyret	Glecaprevir (50 mg/1) + Pibrentasvir (20 mg/1)	Pellet	Oral	AbbVie Inc.	2021-06-10	Not applicable

Categories

ATC Codes

J05AP57 — Glecaprevir and pibrentasvir

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

Drug Categories

• Acids, Acyclic
• Amides
• Amino Acids
• Amino Acids, Branched-Chain
• Amino Acids, Cyclic
• Amino Acids, Essential
• Amino Acids, Peptides, and Proteins
• Aminobutyrates
• Antiinfectives for Systemic Use
• Antiviral Agents
• Antivirals for Systemic Use
• Antivirals for treatment of HCV infections
• BCRP/ABCG2 Inhibitors
• BCRP/ABCG2 Substrates
• Butyrates
• Cycloparaffins
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (weak)
• Cytochrome P-450 Enzyme Inhibitors
• Direct Acting Antivirals
• HCV NS3/4A Protease Inhibitors
• Heterocyclic Compounds, Fused-Ring
• Imino Acids
• Isobutyrates
• Lactams
• NS3/4A Protease Inhibitors
• OATP1B1/SLCO1B1 Inhibitors
• OATP1B1/SLCO1B1 Substrates
• OATP1B3 inhibitors
• OATP1B3 substrates
• Organic Anion Transporting Polypeptide 1B1 Inhibitors
• Organic Anion Transporting Polypeptide 1B3 Inhibitors
• P-glycoprotein inhibitors
• P-glycoprotein substrates
• Sulfones
• Sulfur Compounds
• Treatments for Hepatitis C
• UGT1A1 Inhibitors

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as cyclic peptides. These are compounds containing a cyclic moiety bearing a peptide backbone.

Kingdom

Organic compounds

Super Class

Organic acids and derivatives

Class

Carboxylic acids and derivatives

Sub Class

Amino acids, peptides, and analogues

Direct Parent

Cyclic peptides

Alternative Parents

Macrolactams / N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / Quinoxalines / Pyrrolidinecarboxamides / Alkyl aryl ethers / Pyrazines / Benzenoids / Cyclopropanecarboxylic acids and derivatives / Tertiary carboxylic acid amides / Aminosulfonyl compounds / Carbamate esters / Organosulfonic acids and derivatives / Heteroaromatic compounds / Secondary carboxylic acid amides / Lactams / Azacyclic compounds / Dialkyl ethers / Oxacyclic compounds / Hydrocarbon derivatives / Alkyl fluorides / Carbonyl compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Organofluorides

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Substituents

Alkyl aryl ether / Alkyl fluoride / Alkyl halide / Alpha-amino acid amide / Alpha-amino acid or derivatives / Aminosulfonyl compound / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carbamic acid ester / Carbonyl group / Carboxamide group / Cyclic alpha peptide / Cyclopropanecarboxylic acid or derivatives / Dialkyl ether / Diazanaphthalene / Ether / Heteroaromatic compound / Hydrocarbon derivative / Lactam / Macrolactam / N-acyl-alpha amino acid or derivatives / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organic sulfonic acid or derivatives / Organofluoride / Organohalogen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Organosulfonic acid or derivatives / Organosulfur compound / Oxacycle / Pyrazine / Pyrrolidine / Pyrrolidine carboxylic acid or derivatives / Pyrrolidine-2-carboxamide / Quinoxaline / Secondary carboxylic acid amide / Sulfonyl / Tertiary carboxylic acid amide

show 33 more

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

• Hepatitis C Virus

Chemical Identifiers

UNII

K6BUU8J72P

CAS number

1365970-03-1

InChI Key

MLSQGNCUYAMAHD-ITNVBOSISA-N

InChI

InChI=1S/C38H46F4N6O9S/c1-35(2,3)28-32(50)48-19-20(17-24(48)30(49)46-37(18-21(37)29(39)40)33(51)47-58(53,54)36(4)14-15-36)56-31-27(43-22-9-5-6-10-23(22)44-31)38(41,42)13-8-16-55-25-11-7-12-26(25)57-34(52)45-28/h5-6,8-10,13,20-21,24-26,28-29H,7,11-12,14-19H2,1-4H3,(H,45,52)(H,46,49)(H,47,51)/b13-8+/t20-,21+,24+,25-,26-,28-,37-/m1/s1

IUPAC Name

(1R,14E,18R,22R,26S,29S)-26-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-13,13-difluoro-24,27-dioxo-2,17,23-trioxa-4,11,25,28-tetraazapentacyclo[26.2.1.0^{3,12}.0^{5,10}.0^{18,22}]hentriaconta-3,5(10),6,8,11,14-hexaene-29-carboxamide

SMILES

[H][C@@]12CN(C(=O)[C@@]([H])(NC(=O)O[C@]3([H])CCC[C@@]3([H])OC\C=C\C(F)(F)C3=NC4=C(C=CC=C4)N=C3O1)C(C)(C)C)[C@@]([H])(C2)C(=O)N[C@@]1(C[C@H]1C(F)F)C(=O)NS(=O)(=O)C1(C)CC1

References

General References

1. Salam KA, Akimitsu N: Hepatitis C virus NS3 inhibitors: current and future perspectives. Biomed Res Int. 2013;2013:467869. doi: 10.1155/2013/467869. Epub 2013 Oct 27. [Article]
2. FDA Press Announcements: FDA approves Mavyret for Hepatitis C [Link]
3. FDA Approved Drug Products: MAVYRET (glecaprevir and pibrentasvir) tablets or pellets, for oral use [Link]
4. Health Canada Approved Drug Products: MAVYRET (glecaprevir and pibrentasvir) tablets and granules, for oral use [Link]

External Links

KEGG Drug

D10814

PubChem Compound

66828839

PubChem Substance

347829330

ChemSpider

35013015

RxNav

1940635

ChEMBL

CHEMBL3545363

ZINC

ZINC000164528615

PDBe Ligand

O31

Wikipedia

Glecaprevir

PDB Entries

6p6l / 6p6m / 6p6o / 6p6r / 6p6s / 6p6t / 6p6v / 6p6z / 6vdl / 6vdm

FDA label

Download (925 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Basic Science	Cardiovascular Disease (CVD) / Hepatitis C Virus (HCV) Infection / Human Immunodeficiency Virus (HIV) Infections	1
4	Active Not Recruiting	Treatment	End Stage Renal Disease (ESRD) / Hepatitis C Virus (HCV) Infection	1
4	Active Not Recruiting	Treatment	Heart Transplant Infection / Hepatitis C Virus (HCV) Infection / Transplanted Kidney Complication	1
4	Completed	Prevention	Hepatitis C Virus (HCV) Infection / Renal Failure, Chronic Renal Failure	1
4	Completed	Treatment	Chronic Hepatitis C Virus (HCV) Infection / Chronic Kidney Disease (CKD)	1
4	Completed	Treatment	End Stage Renal Disease (ESRD) / Hepatitis C Virus (HCV) Infection	1
4	Recruiting	Treatment	Chronic Kidney Disease (CKD) / Hepatitis C Virus (HCV) Infection / Kidney Failure	1
4	Recruiting	Treatment	Hepatitis C Virus (HCV) Infection	2
4	Terminated	Prevention	Hepatitis C Virus (HCV) Infection / Respiratory Failure	1
4	Unknown Status	Treatment	Addict Heroin / Hepatitis C Virus (HCV) Infection	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Granule	Oral
Tablet	Oral
Tablet, coated	Oral
Tablet, film coated	Oral	100.0 mg
Pellet	Oral
Tablet, film coated	Oral

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9586978	Yes	2017-03-07	2030-12-10
US8648037	Yes	2014-02-11	2032-07-19
US9321807	Yes	2016-04-26	2035-12-05
US8937150	Yes	2015-01-20	2032-11-18
US10039754	Yes	2018-08-07	2030-12-10
US10028937	Yes	2018-07-24	2030-12-10
US10286029	Yes	2019-05-14	2034-09-14
USRE48923	Yes	2015-11-08	2035-11-08
US11246866	Yes	2016-12-24	2036-12-24
US11484534	Yes	2014-09-14	2034-09-14

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	<0.1 to 0.3 mg/mL	FDA Label

Predicted Properties

Property	Value	Source
Water Solubility	0.0463 mg/mL	ALOGPS
logP	4.26	ALOGPS
logP	3.95	Chemaxon
logS	-4.3	ALOGPS
pKa (Strongest Acidic)	3.74	Chemaxon
pKa (Strongest Basic)	-1.2	Chemaxon
Physiological Charge	-1	Chemaxon
Hydrogen Acceptor Count	10	Chemaxon
Hydrogen Donor Count	3	Chemaxon
Polar Surface Area	195.22 Å2	Chemaxon
Rotatable Bond Count	6	Chemaxon
Refractivity	194.55 m3·mol-1	Chemaxon
Polarizability	78.89 Å3	Chemaxon
Number of Rings	7	Chemaxon
Bioavailability	1	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

Not Available

Targets

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Details1. NS3 protease

Kind

Protein

Organism

Hepatitis C Virus

Pharmacological action

Yes

Actions

Inhibitor

General Function

Serine-type peptidase activity

Specific Function

Not Available

Gene Name

Not Available

Uniprot ID

Q91RS4

Uniprot Name

NS3 protease

Molecular Weight

19113.77 Da

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Drug created at August 31, 2017 15:33 / Updated at July 02, 2022 12:49