Velpatasvir

Identification

Summary

Velpatasvir is a NS5A inhibitor used to treat chronic hepatitis C infections in patients without cirrhosis or with compensated cirrhosis.

Brand Names
Epclusa, Vosevi
Generic Name
Velpatasvir
DrugBank Accession Number
DB11613
Background

Velpatasvir is a Direct-Acting Antiviral (DAA) 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 8. Velpatasvir acts as a defective substrate for NS5A (Non-Structural Protein 5A), a non-enzymatic viral protein that plays a key role in Hepatitis C Virus replication, assembly, and modulation of host immune responses 3. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as velpatasvir. Notably, velpatasvir has a significantly higher barrier to resistance than the first generation NS5A inhibitors, such as Ledipasvir and Daclatasvir, making it a highly potent and reliable alternative for treatment of chronic Hepatitis C 6.

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 Velpatasvir as first line therapy in combination with sofosbuvir for all six genotypes of Hepatitis C 8. Velpatasvir is currently only available within a fixed dose combination product as Epclusa with Sofosbuvir, another direct acting antiviral. Goals of therapy for Epclusa include 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 and risk of requiring a liver transplant 5.

Since June 2016, Velpatasvir has been available as a fixed dose combination product with Sofosbuvir, as the commercially available product Epclusa. Epclusa is the first combination HCV product indicated for the treatment of all genotypes of Hepatitis C with or without cirrhosis. It is also currently the most potent HCV antiviral medication on the market with a sustained virologic response (SVR) after 12 weeks of therapy of 93-99% depending on genotype and level of cirrhosis and a high barrier to resistance 8. Both Canadian and American guidelines list Epclusa as a first line recommendation for all genotypes of HCV 8,5.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 883.019
Monoisotopic: 882.406460731
Chemical Formula
C49H54N8O8
Synonyms
  • Velpatasvir
  • Velpatasvirum
External IDs
  • GS 5816
  • GS-5816
  • GS5816

Pharmacology

Indication

Velpatasvir is used in combination therapy with other antiviral medications to treat chronic hepatitis C virus (HCV) infected patients with HCV genoptypes 1-6, and to treat HCV and HIV co-infected patients. Depending on the level of cirrhosis or decompensation, combination therapy can also include therapy with Ribavirin.

When used in combination with Sofosbuvir as the combination product Epclusa, Velpatasvir is 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, or in combination with Ribavirin if associated with decompensated cirrhosis Label.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatChronic hepatitis c genotype 1Regimen in combination with: Sofosbuvir (DB08934)••••••••••••
Used in combination to treatChronic hepatitis c genotype 2Regimen in combination with: Sofosbuvir (DB08934)••••••••••••
Used in combination to treatChronic hepatitis c genotype 3Regimen in combination with: Sofosbuvir (DB08934)••••••••••••
Used in combination to treatChronic hepatitis c genotype 4Regimen in combination with: Sofosbuvir (DB08934)••••••••••••
Used in combination to treatChronic hepatitis c genotype 5Regimen in combination with: Sofosbuvir (DB08934)••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Velpatasvir is a small molecule direct-acting antiviral used in the treatment of hepatitis C in combination with sofosbuvir. Velpatasvir prevents viral replication by inhibiting non-structural protein 5A (NS5A) 4.

At a dose 5 times the recommended dose, velpatasvir does not prolong QTc interval to any clinically relevant extent Label.

Mechanism of action

Velpatasvir's mechanism of action is likely similar to other selective NS5A inhibitors which bind domain I of NS5A consisting of amino acids 33-202 1. NS5A inhibitors compete with RNA for binding at this site. It is also thought that NS5A inhibitors bind the target during its action in replication when the binding site is exposed 2. Inhibition of NS5A is also known to produce redistribution of the protein to lipid droplets. The exact role of NS5A in RNA replication is not yet understood although it is known to be an important component.

TargetActionsOrganism
ANonstructural protein 5A
inhibitor
Hepatitis C Virus
Absorption

Oral bioavailability of 25-30% 3.

Volume of distribution

1.4-1.6 L/kg 3.

Protein binding

>99.5% bound to plasma proteins Label.

Metabolism

Some metabolism by CYP2B6, CYP2C8, and CYP3A4 3.

Route of elimination

94% excreted in feces with 77% as parent compound. 0.4% excreted in urine Label.

Half-life

15h Label.

Clearance

Estimated 0.12 L/h/kg [A19175.

Adverse Effects
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Toxicity

No indication of carcinogenicity or impairment of fertility/fetal viability 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.
DrugInteraction
AbametapirThe serum concentration of Velpatasvir can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Velpatasvir can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Velpatasvir.
AbirateroneThe metabolism of Velpatasvir can be decreased when combined with Abiraterone.
AbrocitinibThe serum concentration of Velpatasvir can be increased when it is combined with Abrocitinib.
Food Interactions
  • Avoid St. John's Wort.
  • Take with or without food. Multiple different combination products contain velpatasvir. Take Epclusa with or without food. Take Vosevi with food.

Products

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
EpclusaVelpatasvir (100 mg) + Sofosbuvir (400 mg)Tablet, film coatedOralGilead Sciences Ireland Uc2016-09-08Not applicableEU flag
EpclusaVelpatasvir (50 mg/1) + Sofosbuvir (200 mg/1)Tablet, film coatedOralGilead Sciences, Inc.2020-03-19Not applicableUS flag
EPCLUSAVelpatasvir (50 MG) + Sofosbuvir (200 MG)Tablet, film coatedOralGilead Sciences Ireland Uc2020-11-17Not applicableItaly flag
EpclusaVelpatasvir (37.5 mg/1) + Sofosbuvir (150 mg/1)PelletOralGilead Sciences, Inc.2021-06-10Not applicableUS flag
EpclusaVelpatasvir (100 mg/1) + Sofosbuvir (400 mg/1)Tablet, film coatedOralGilead Sciences, Inc.2016-06-28Not applicableUS flag

Categories

ATC Codes
J05AP55 — Sofosbuvir and velpatasvirJ05AP56 — Sofosbuvir, velpatasvir and voxilaprevir
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as naphthopyrans. These are compounds containing a pyran ring fused to a naphthalene moiety. Furan is a 6 membered-ring non-aromatic ring with five carbon and one oxygen atoms. Naphthalene is a polycyclic aromatic hydrocarbon made up of two fused benzene rings.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Naphthopyrans
Sub Class
Not Available
Direct Parent
Naphthopyrans
Alternative Parents
Dibenzopyrans / Valine and derivatives / Alpha amino acid amides / Phenylacetamides / 2-benzopyrans / Naphthalenes / Benzimidazoles / N-acylpyrrolidines / Alkyl aryl ethers / Pyrans
show 12 more
Substituents
1-benzopyran / 2-benzopyran / Alkyl aryl ether / Alpha-amino acid amide / Alpha-amino acid or derivatives / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Benzimidazole
show 28 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Hepatitis C Virus

Chemical Identifiers

UNII
KCU0C7RS7Z
CAS number
1377049-84-7
InChI Key
FHCUMDQMBHQXKK-CDIODLITSA-N
InChI
InChI=1S/C49H54N8O8/c1-26(2)41(54-48(60)63-5)47(59)57-27(3)12-17-38(57)45-51-36-16-14-30-20-35-33-15-13-31(19-32(33)25-65-40(35)21-34(30)43(36)53-45)37-22-50-44(52-37)39-18-28(24-62-4)23-56(39)46(58)42(55-49(61)64-6)29-10-8-7-9-11-29/h7-11,13-16,19-22,26-28,38-39,41-42H,12,17-18,23-25H2,1-6H3,(H,50,52)(H,51,53)(H,54,60)(H,55,61)/t27-,28-,38-,39-,41-,42+/m0/s1
IUPAC Name
methyl N-[(1R)-2-[(2S,4S)-2-(5-{6-[(2S,5S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl]-5-methylpyrrolidin-2-yl]-21-oxa-5,7-diazapentacyclo[11.8.0.0^{3,11}.0^{4,8}.0^{14,19}]henicosa-1,3(11),4(8),6,9,12,14,16,18-nonaen-17-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl]carbamate
SMILES
COC[C@H]1C[C@H](N(C1)C(=O)[C@H](NC(=O)OC)C1=CC=CC=C1)C1=NC=C(N1)C1=CC=C2C(COC3=CC4=C(C=CC5=C4NC(=N5)[C@@H]4CC[C@H](C)N4C(=O)[C@@H](NC(=O)OC)C(C)C)C=C23)=C1

References

General References
  1. Ascher DB, Wielens J, Nero TL, Doughty L, Morton CJ, Parker MW: Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA. Sci Rep. 2014 Apr 23;4:4765. doi: 10.1038/srep04765. [Article]
  2. Targett-Adams P, Graham EJ, Middleton J, Palmer A, Shaw SM, Lavender H, Brain P, Tran TD, Jones LH, Wakenhut F, Stammen B, Pryde D, Pickford C, Westby M: Small molecules targeting hepatitis C virus-encoded NS5A cause subcellular redistribution of their target: insights into compound modes of action. J Virol. 2011 Jul;85(13):6353-68. doi: 10.1128/JVI.00215-11. Epub 2011 Apr 20. [Article]
  3. Mogalian E, German P, Kearney BP, Yang CY, Brainard D, Link J, McNally J, Han L, Ling J, Mathias A: Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects. Antimicrob Agents Chemother. 2017 Apr 24;61(5). pii: e02084-16. doi: 10.1128/AAC.02084-16. Print 2017 May. [Article]
  4. Lawitz E, Freilich B, Link J, German P, Mo H, Han L, Brainard DM, McNally J, Marbury T, Rodriguez-Torres M: A phase 1, randomized, dose-ranging study of GS-5816, a once-daily NS5A inhibitor, in patients with genotype 1-4 hepatitis C virus. J Viral Hepat. 2015 Dec;22(12):1011-9. doi: 10.1111/jvh.12435. Epub 2015 Jul 16. [Article]
  5. 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]
  6. Lawitz EJ, Dvory-Sobol H, Doehle BP, Worth AS, McNally J, Brainard DM, Link JO, Miller MD, Mo H: Clinical Resistance to Velpatasvir (GS-5816), a Novel Pan-Genotypic Inhibitor of the Hepatitis C Virus NS5A Protein. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5368-78. doi: 10.1128/AAC.00763-16. Print 2016 Sep. [Article]
  7. Epclusa FDA Approval Announcement [Link]
  8. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance. http://hcvguidelines.org. Accessed June 12, 2017. [Link]
KEGG Drug
D10806
PubChem Compound
67683363
PubChem Substance
347828007
ChemSpider
34501056
RxNav
1799206
ChEBI
133009
ChEMBL
CHEMBL3545062
ZINC
ZINC000203686879
PharmGKB
PA166163415
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Velpatasvir
FDA label
Download (338 KB)
MSDS
Download (243 KB)

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
PelletOral
TabletOral
Tablet, film coatedOral
Tablet, coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7964580Yes2011-06-212029-09-26US flag
US8334270Yes2012-12-182028-09-21US flag
US8633309Yes2014-01-212029-09-26US flag
US8618076Yes2013-12-312031-06-11US flag
US8735372Yes2014-05-272028-09-21US flag
US8580765Yes2013-11-122028-09-21US flag
US8889159Yes2014-11-182029-09-26US flag
US9085573Yes2015-07-212028-09-21US flag
US9284342Yes2016-03-152031-03-13US flag
US8940718Yes2015-01-272033-05-16US flag
US8575135Yes2013-11-052034-05-05US flag
US8921341Yes2014-12-302033-05-16US flag
US9585906No2017-03-072028-03-21US flag
US9296782No2016-03-292034-07-17US flag
US9757406Yes2017-09-122034-07-30US flag
US9868745No2018-01-162032-11-16US flag
US10086011Yes2018-10-022034-07-30US flag
US8957046No2015-02-172028-03-21US flag
US10912814No2021-02-092037-06-01US flag
US11116783Yes2021-09-142034-07-30US flag
US11338007Yes2017-12-012037-12-01US flag
US11707479Yes2014-07-302034-07-30US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00585 mg/mLALOGPS
logP5.39ALOGPS
logP5.11Chemaxon
logS-5.2ALOGPS
pKa (Strongest Acidic)11.14Chemaxon
pKa (Strongest Basic)5.97Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count8Chemaxon
Hydrogen Donor Count4Chemaxon
Polar Surface Area193.1 Å2Chemaxon
Rotatable Bond Count13Chemaxon
Refractivity240.57 m3·mol-1Chemaxon
Polarizability97.05 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/MSsplash10-01e9-0200000590-24093dc5374d2023160e
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0229-3200002490-0dc768065484be0b4c16
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0fb9-1000003970-ed3c6b83279a3e8dcd8a
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0296-3000001950-987503e33edc80166cb1
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0ac0-9510001250-983e4230aae36bbc1820
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-01po-1121007940-b7d276d88cf7c3ed5de8
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-273.1923
predicted
DeepCCS 1.0 (2019)
[M+H]+274.96066
predicted
DeepCCS 1.0 (2019)
[M+Na]+281.0851
predicted
DeepCCS 1.0 (2019)

Targets

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Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
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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
No
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Sofosbuvir and Velpatasvir FDA Label [File]
  2. Sofosbuvir and Velpatasvir EMA Label [File]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. VOSEVI (sofosbuvir, velpatasvir, and voxilaprevir) FDA Label [File]
Kind
Protein
Organism
Humans
Pharmacological action
No
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

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
References
  1. Mogalian E, German P, Kearney BP, Yang CY, Brainard D, McNally J, Moorehead L, Mathias A: Use of Multiple Probes to Assess Transporter- and Cytochrome P450-Mediated Drug-Drug Interaction Potential of the Pangenotypic HCV NS5A Inhibitor Velpatasvir. Clin Pharmacokinet. 2016 May;55(5):605-13. doi: 10.1007/s40262-015-0334-7. [Article]
  2. Geddawy A, Ibrahim YF, Elbahie NM, Ibrahim MA: Direct Acting Anti-hepatitis C Virus Drugs: Clinical Pharmacology and Future Direction. J Transl Int Med. 2017 Mar 31;5(1):8-17. doi: 10.1515/jtim-2017-0007. eCollection 2017 Mar. [Article]
  3. FDA label Sofusbuvir and Velpatasvir [File]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Transporter
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Transporter
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Transporter
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost.
Gene Name
SLCO2B1
Uniprot ID
O94956
Uniprot Name
Solute carrier organic anion transporter family member 2B1
Molecular Weight
76709.98 Da

Drug created at August 05, 2016 23:48 / Updated at February 21, 2021 18:53