Identification

Name
Voxilaprevir
Accession Number
DB12026
Type
Small Molecule
Groups
Approved, Investigational
Description

Voxilaprevir 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 [3].

Voxilaprevir exerts its antiviral action by reversibly binding and inhibiting the NS3/4A serine protease of Hepatitis C Virus (HCV) [Label]. Following viral replication of HCV genetic material and translation into a single polypeptide, Nonstructural Protein 3 (NS3) and its activating cofactor Nonstructural Protein 4A (NS4A) are responsible for cleaving genetic material into the following structural and nonstructural proteins required for assembly into mature virus: NS3, NS4A, NS4B, NS5A, and NS5B [2]. By inhibiting viral protease NS3/4A, voxilaprevir therefore prevents viral replication and function. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as voxilaprevir.

Voxilaprevir has been available since July 2017 in a fixed dose combination product with Sofosbuvir and Velpatasvir as the commercially available product Vosevi. Vosevi is approved for the treatment of adult patients with chronic HCV infection with genotype 1, 2, 3, 4, 5, or 6 infection [Label]. Notably, Vosevi is approved for use in patients with genotypes 1-6 who have been previously treated with an NS5A inhibitor, or patients with genotypes 1a or 3 infection and have previously been treated with an HCV regimen containing Sofosbuvir without an NS5A inhibitor [4]. Prior to Vosevi, there were no approved retreatment options for patients who have previously received, and failed, a regimen containing an NS5A inhibitor for treatment of chronic HCV infection.

Structure
Thumb
Synonyms
Not Available
External IDs
GS 9857 / GS-9857 / GS9857
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
VoseviVoxilaprevir (100 mg) + Sofosbuvir (400 mg) + Velpatasvir (100 mg)TabletOralGilead Sciences2017-09-18Not applicableCanada
VoseviVoxilaprevir (100 mg/1) + Sofosbuvir (400 mg/1) + Velpatasvir (100 mg/1)Tablet, film coatedOralGilead Sciences2017-07-18Not applicableUs
Categories
UNII
0570F37359
CAS number
1535212-07-7
Weight
Average: 868.94
Monoisotopic: 868.345261104
Chemical Formula
C40H52F4N6O9S
InChI Key
MZBLZLWXUBZHSL-FZNJKFJKSA-N
InChI
InChI=1S/C40H52F4N6O9S/c1-7-22-27-19-50(28(22)32(51)48-39(18-23(39)31(41)42)35(53)49-60(55,56)38(5)14-15-38)34(52)30(37(2,3)4)47-36(54)59-26-16-20(26)10-8-9-13-40(43,44)29-33(58-27)46-25-17-21(57-6)11-12-24(25)45-29/h11-12,17,20,22-23,26-28,30-31H,7-10,13-16,18-19H2,1-6H3,(H,47,54)(H,48,51)(H,49,53)/t20-,22-,23+,26-,27+,28+,30-,39-/m1/s1
IUPAC Name
(1R,18R,20R,24S,27S,28S)-24-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-28-ethyl-13,13-difluoro-7-methoxy-22,25-dioxo-2,21-dioxa-4,11,23,26-tetraazapentacyclo[24.2.1.0^{3,12}.0^{5,10}.0^{18,20}]nonacosa-3(12),4,6,8,10-pentaene-27-carboxamide
SMILES
CC[C@@H]1[C@@H]2CN([C@@H]1C(=O)N[C@@]1(C[C@H]1C(F)F)C(=O)NS(=O)(=O)C1(C)CC1)C(=O)[C@@H](NC(=O)O[C@@H]1C[C@H]1CCCCC(F)(F)C1=C(O2)N=C2C=C(OC)C=CC2=N1)C(C)(C)C

Pharmacology

Indication

Vosevi (Voxilaprevir/Sofosbuvir/Velpatasvir) is approved for use in patients with genotypes 1-6 who have been previously treated with an NS5A inhibitor, or patients with genotypes 1a or 3 infection who have previously been treated with an HCV regimen containing Sofosbuvir without an NS5A inhibitor [4].

Associated Conditions
Pharmacodynamics

Voxilaprevir is a direct-acting antiviral agent that targets viral NS3/4A protein and causes a decrease in serum HCV RNA levels. It disrupts HCV replication by specifically inhibiting the critical functions of NS3/4A protein in the replication complex. It does not appear to prolong the QT interval even when given at 9 times the maximum recommended dose [Label].

Mechanism of action

Voxilaprevir exerts its antiviral action by reversibley binding and inhibiting the NS3/4A serine protease of Hepatitis C Virus (HCV) [Label]. Following viral replication of HCV genetic material and translation into a single polypeptide, Nonstructural Protein 3 (NS3) and its activating cofactor Nonstructural Protein 4A (NS4A) are responsible for cleaving genetic material into the following structural and nonstructural proteins required for assembly into mature virus: NS3, NS4A, NS4B, NS5A, and NS5B [2]. By inhibiting viral protease NS3/4A, voxilaprevir therefore prevents viral replication and function.

TargetActionsOrganism
ANS3/4A protein
inhibitor
Hepatitis C virus
Absorption

When provided as the fixed dose combination product Vosevi with Sofosbuvir and Velpatasvir, voxilaprevir reaches a maximum concentration (Cmax) of 192 ng/mL at a maximum time (Tmax) of 4 hours post-dose [Label].

Volume of distribution
Not Available
Protein binding

Voxilaprevir is more than 99% bound to human plasma proteins [Label].

Metabolism

Voxilaprevir is primarily metabolized by Cytochrome P450 3A4 (CYP3A4) and to a lesser extent by CYP2C8 and CYP1A2[Label].

Route of elimination

Voxilaprevir is primarily eliminated via biliary excretion [Label].

Half life

33 hr [Label]

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Voxilaprevir can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Voxilaprevir.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be increased when it is combined with Voxilaprevir.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Voxilaprevir.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Voxilaprevir.
5-androstenedioneThe metabolism of Voxilaprevir can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Voxilaprevir can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe serum concentration of 6-O-benzylguanine can be increased when it is combined with Voxilaprevir.
7-DeazaguanineThe serum concentration of 7-Deazaguanine can be increased when it is combined with Voxilaprevir.
7,9-DimethylguanineThe serum concentration of 7,9-Dimethylguanine can be increased when it is combined with Voxilaprevir.
Food Interactions
Not Available

References

General References
  1. Bourliere M, Gordon SC, Flamm SL, Cooper CL, Ramji A, Tong M, Ravendhran N, Vierling JM, Tran TT, Pianko S, Bansal MB, de Ledinghen V, Hyland RH, Stamm LM, Dvory-Sobol H, Svarovskaia E, Zhang J, Huang KC, Subramanian GM, Brainard DM, McHutchison JG, Verna EC, Buggisch P, Landis CS, Younes ZH, Curry MP, Strasser SI, Schiff ER, Reddy KR, Manns MP, Kowdley KV, Zeuzem S: Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med. 2017 Jun 1;376(22):2134-2146. doi: 10.1056/NEJMoa1613512. [PubMed:28564569]
  2. Moradpour D, Penin F: Hepatitis C virus proteins: from structure to function. Curr Top Microbiol Immunol. 2013;369:113-42. doi: 10.1007/978-3-642-27340-7_5. [PubMed:23463199]
  3. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance. http://hcvguidelines.org. Accessed June 12, 2017. [Link]
  4. FDA News Release: FDA approves Vosevi for Hepatitis C [Link]
External Links
PubChem Compound
89921642
PubChem Substance
347828341
ChemSpider
44209500
ChEMBL
CHEMBL3707372
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Voxilaprevir
FDA label
Download (1.34 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHepatitis C Virus (HCV) Infection3
1CompletedTreatmentHepatitis C Virus Infection1
2CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection2
2CompletedTreatmentHepatitis C Virus Infection3
3Active Not RecruitingTreatmentHepatitis C Virus Infection1
3CompletedTreatmentHepatitis C Viral Infection2
3CompletedTreatmentHepatitis C Virus Infection2
4Active Not RecruitingTreatmentHCV Coinfection / Human Immunodeficiency Virus (HIV) / Liver Diseases1
4RecruitingOtherHepatitis C Viral Infection / Transplantation Disease Transmission1
Not AvailableEnrolling by InvitationNot AvailableHepatitis C Virus Infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7964580No2011-06-212029-03-26Us
US8334270No2012-12-182028-03-21Us
US8633309No2014-01-212029-03-26Us
US8618076No2013-12-312030-12-11Us
US8735372No2014-05-272028-03-21Us
US8580765No2013-11-122028-03-21Us
US8889159No2014-11-182029-03-26Us
US9085573No2015-07-212028-03-21Us
US9284342No2016-03-152030-09-13Us
US8940718No2015-01-272032-11-16Us
US8575135No2013-11-052032-11-16Us
US8921341No2014-12-302032-11-16Us
US9585906No2017-03-072028-03-21Us
US9296782No2016-03-292034-07-17Us
US9868745No2018-01-162032-11-16Us

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0506 mg/mLALOGPS
logP3.98ALOGPS
logP4.9ChemAxon
logS-4.2ALOGPS
pKa (Strongest Acidic)3.74ChemAxon
pKa (Strongest Basic)-0.84ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area195.22 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity203.02 m3·mol-1ChemAxon
Polarizability85.37 Å3ChemAxon
Number of Rings7ChemAxon
Bioavailability1ChemAxon
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 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 / Anisoles / Alkyl aryl ethers / Pyrazines / Cyclopropanecarboxylic acids and derivatives / Tertiary carboxylic acid amides
show 15 more
Substituents
Cyclic alpha peptide / Macrolactam / N-acyl-alpha amino acid or derivatives / Alpha-amino acid amide / Diazanaphthalene / Alpha-amino acid or derivatives / Quinoxaline / Anisole / Phenol ether / Pyrrolidine carboxylic acid or derivatives
show 34 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Hepatitis C virus
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type peptidase activity
Specific Function
Not Available
Gene Name
NS3/4A
Uniprot ID
B0B3C9
Uniprot Name
Genome polyprotein
Molecular Weight
72789.28 Da

Enzymes

Kind
Protein
Organism
Human
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
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Voxilaprevir FDA label [File]
  2. Management of Unique Populations with HCV Infection [File]
Kind
Protein
Organism
Human
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]

Transporters

Kind
Protein
Organism
Human
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
Kind
Protein
Organism
Human
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
Human
Pharmacological action
No
Actions
Substrate
Inhibitor
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
Human
Pharmacological action
No
Actions
Substrate
Inhibitor
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

Drug created on October 20, 2016 15:12 / Updated on November 02, 2018 07:19