Boceprevir

Identification

Summary

Boceprevir is a hepatitis C virus NS3/4A protease inhibitor used in combination with other medications to treat chronic hepatitis C genotype 1 infection. Boceprevir is not indicated as monotherapy.

Generic Name
Boceprevir
DrugBank Accession Number
DB08873
Background

Boceprevir 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 7. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as Boceprevir. Boceprevir is an inhibitor of NS3/4A, a serine protease enzyme, encoded by HCV genotypes 1 and 4 Synthesis. These enzymes are essential for viral replication and serve to cleave the virally encoded polyprotein into mature proteins like NS4A, NS4B, NS5A and NS5B Label. The barrier for develoment of resistance to NS3/4A inhibitors is lower than that of NS5B inhibitors, another class of DAAs 5. Subtitutions at amino acid positions 155, 156, or 168 are known to confer resistance. The substitutions of the enzyme's catalytic triad consisting of H58, D82, and S139 are also likely to alter the affinity of the drug for NS3/4A or the activity of the enzyme itself. Despite this disadvantage Boceprevir is still effective against HCV when paired with Ribavirin, Peginterferon alfa-2a, and Peginterferon alfa-2b.

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) do not reccomend Boceprevir in combination with Ribavirin, Peginterferon alfa-2a, and Peginterferon alfa-2b as first line therapy for Hepatitis C 5. Boceprevir, Ribavirin, Peginterferon alfa-2a, and Peginterferon alfa-2b are used with the intent to cure, or achieve a sustained virologic response (SVR), after 48 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 6.

Boceprevir is available as a fixed dose product (tradename Victrelis) used for the treatment of chronic Hepatitis C. Approved in May 2011 by the FDA, Victrelis is indicated for the treatment of HCV genotype 1 in combination with Ribavirin, Peginterferon alfa-2a, and Peginterferon alfa-2b Label. Victrelis is no longer widely used as interferon-free therapies have been developed.

Type
Small Molecule
Groups
Approved, Withdrawn
Structure
Weight
Average: 519.6767
Monoisotopic: 519.342069575
Chemical Formula
C27H45N5O5
Synonyms
  • Boceprevir
External IDs
  • EBP 520
  • EBP-520
  • SCH 503034
  • SCH-503034

Pharmacology

Indication

Boceprevir, when used in combination with Ribavirin, Peginterferon alfa-2a, and Peginterferon alfa-2b is indicated for use in the treatment of chronic HCV genotype 1 infection in adults Label.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatChronic hepatitis c genotype 1Combination Product in combination with: Peginterferon alfa-2b (DB00022), Ribavirin (DB00811)••••••••••••
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Pharmacodynamics

Boceprevir is classified as a direct-acting antiviral (DAA) and prevents viral replication in HCV genotype 1 Label.

Mechanism of action

Boceprevir is a NS3/4a protease inhibitor used to inhibit viral HCV replication Label. NS3/4a protease is an integral part of viral replication and mediates the cleavage the virally encoded polyprotein to mature proteins (NS4A, NS4B, NS5A and NS5B) Label. Boceprevir covalently but reversibly binds the serine (S139) resiude in the active site via a (α)-ketoamide functional group. This inhibits the proteolytic acitvity of the HCV 1a and 1b encoded enzyme.

TargetActionsOrganism
ANS3/4A protein
inhibitor
Hepatitis C Virus
Absorption

Boceprevir reaches peak plasma concentration 2 hours after administration Label. Absolute bioavailability has not been determined. When taken with food exposure increases up to 65%. In capsule, Boceprevir consists of two diaseromers in a 1:1 ratio. In plasma this ratio changes to 2:1 favoring the active diastereomer.

Volume of distribution

The mean apparent volume of distribution for Bocepravir is 772 litres at steady state Label.

Protein binding

Bocepravir is approximately 75% bound to human plasma proteins following a single dose Label.

Metabolism

Bocepravir is primarily metabolized via the aldo-ketoreductase-mediated pathway producing a diastereomeric mix of metabolites at a 4 fold greater exposure than the parent compound Label. Boceprevir also undergoes oxidative metabolism via CYP3A4/5, although to a lesser extent.

Route of elimination

Boceprevir is mainly eliminated in the feces (79%) with a small amount eliminated in the urine (9%) Label. Approximately 8% and 3% is excreted as the parent compound in the feces and urine respectively.

Half-life

Boceprevir has a mean half-life of elimination of 3.4 hours Label.

Clearance

Boceprevir has a mean total body clearance of 161 liters per hour Label.

Adverse Effects
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Toxicity

The most commonly reported adverse reactions in adult subjects were fatigue, anemia, nausea, headache, and dysgeusia when Boceprevir was used in combination with Ribavirin and Peginterferon alfa-2a/Peginterferon alfa-2b 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
1,2-BenzodiazepineThe metabolism of 1,2-Benzodiazepine can be decreased when combined with Boceprevir.
AbametapirThe serum concentration of Boceprevir can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Boceprevir can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Boceprevir.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Boceprevir.
Food Interactions
  • Take with or without food. Food decreases drug exposure, but not to a clinically significant extent.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VictrelisCapsule200 mgOralMerck Sharp Dohme Ltd2016-09-082018-07-31EU flag
VictrelisCapsule200 mg/1OralMerck Sharp & Dohme Limited2011-05-132015-12-31US flag
VictrelisCapsule200 mgOralMerck Sharp Dohme Ltd2016-09-082018-07-31EU flag
VictrelisCapsule200 mgOralMerck Ltd.2011-08-022017-01-10Canada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Victrelis TripleBoceprevir (200 mg / cap) + Peginterferon alfa-2b (100 mcg / 0.5 mL) + Ribavirin (200 mg / cap)Capsule; Powder, for solutionOral; SubcutaneousMerck Ltd.2011-08-162017-01-10Canada flag
Victrelis TripleBoceprevir (200 mg / cap) + Peginterferon alfa-2b (120 mcg / 0.5 mL) + Ribavirin (200 mg / cap)Capsule; Powder, for solutionOral; SubcutaneousMerck Ltd.2011-08-162016-09-02Canada flag
Victrelis TripleBoceprevir (200 mg / cap) + Peginterferon alfa-2b (80 mcg / 0.5 mL) + Ribavirin (200 mg / cap)Capsule; Powder, for solutionOral; SubcutaneousMerck Ltd.2011-08-162017-01-10Canada flag
Victrelis TripleBoceprevir (200 mg / cap) + Peginterferon alfa-2b (150 mcg / 0.5 mL) + Ribavirin (200 mg / cap)Capsule; Powder, for solutionOral; SubcutaneousMerck Ltd.2011-08-162016-09-02Canada flag

Categories

ATC Codes
J05AP03 — Boceprevir
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as hybrid peptides. These are compounds containing at least two different types of amino acids (alpha, beta, gamma, delta) linked to each other through a peptide bond.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Peptidomimetics
Sub Class
Hybrid peptides
Direct Parent
Hybrid peptides
Alternative Parents
Dipeptides / Valine and derivatives / N-carbamoyl-alpha amino acids and derivatives / Alpha amino acid amides / Piperidinecarboxamides / N-acylpiperidines / Pyrrolidinecarboxamides / N-acylpyrrolidines / Fatty amides / Tertiary carboxylic acid amides
show 9 more
Substituents
2-piperidinecarboxamide / Aliphatic heteropolycyclic compound / Alpha-amino acid amide / Alpha-amino acid or derivatives / Alpha-dipeptide / Azacycle / Carbonic acid derivative / Carbonyl group / Carboxamide group / Carboxylic acid derivative
show 25 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
ureas, tripeptide (CHEBI:68621)
Affected organisms
  • Hepatitis C Virus

Chemical Identifiers

UNII
89BT58KELH
CAS number
394730-60-0
InChI Key
LHHCSNFAOIFYRV-DOVBMPENSA-N
InChI
InChI=1S/C27H45N5O5/c1-25(2,3)20(30-24(37)31-26(4,5)6)23(36)32-13-15-17(27(15,7)8)18(32)22(35)29-16(19(33)21(28)34)12-14-10-9-11-14/h14-18,20H,9-13H2,1-8H3,(H2,28,34)(H,29,35)(H2,30,31,37)/t15-,16?,17-,18-,20+/m0/s1
IUPAC Name
3-{[(1R,2S,5S)-3-[(2S)-2-[(tert-butylcarbamoyl)amino]-3,3-dimethylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl]formamido}-4-cyclobutyl-2-oxobutanamide
SMILES
[H][C@]12CN([C@H](C(=O)NC(CC3CCC3)C(=O)C(N)=O)[C@@]1([H])C2(C)C)C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C

References

Synthesis Reference

James Lalonde, Tao Li, Jack Liang, Benjamin Mijts, Roger Sheldon, George S.K. Wong, Aleksey Zaks, "Substantially Stereomerically Pure Fused Bicyclic Proline Compounds and Processes for Preparing Boceprevir." U.S. Patent US20120289709, issued November 15, 2012.

US20120289709
General References
  1. Kiser JJ, Flexner C: Direct-acting antiviral agents for hepatitis C virus infection. Annu Rev Pharmacol Toxicol. 2013;53:427-49. doi: 10.1146/annurev-pharmtox-011112-140254. Epub 2012 Nov 5. [Article]
  2. Treitel M, Marbury T, Preston RA, Triantafyllou I, Feely W, O'Mara E, Kasserra C, Gupta S, Hughes EA: Single-dose pharmacokinetics of boceprevir in subjects with impaired hepatic or renal function. Clin Pharmacokinet. 2012 Sep 1;51(9):619-28. doi: 10.2165/11633440-000000000-00000. [Article]
  3. Wilby KJ, Partovi N, Ford JA, Greanya E, Yoshida EM: Review of boceprevir and telaprevir for the treatment of chronic hepatitis C. Can J Gastroenterol. 2012 Apr;26(4):205-10. [Article]
  4. Malcolm BA, Liu R, Lahser F, Agrawal S, Belanger B, Butkiewicz N, Chase R, Gheyas F, Hart A, Hesk D, Ingravallo P, Jiang C, Kong R, Lu J, Pichardo J, Prongay A, Skelton A, Tong X, Venkatraman S, Xia E, Girijavallabhan V, Njoroge FG: SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob Agents Chemother. 2006 Mar;50(3):1013-20. [Article]
  5. 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]
  6. 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]
  7. 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
D08876
PubChem Compound
10324367
PubChem Substance
175427127
ChemSpider
8499830
BindingDB
12311
RxNav
1102129
ChEBI
68621
ChEMBL
CHEMBL218394
PharmGKB
PA165948902
PDBe Ligand
HU5
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Boceprevir
FDA label
Download (403 KB)

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral200 mg
CapsuleOral200 mg/1
Capsule, coatedOral200 mg
Capsule; powder, for solutionOral; Subcutaneous
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7772178No2010-08-102027-11-11US flag
US8119602No2012-02-212027-03-17US flag
USRE43298No2012-04-032022-02-22US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0234 mg/mLALOGPS
logP1.93ALOGPS
logP1.78Chemaxon
logS-4.4ALOGPS
pKa (Strongest Acidic)12.44Chemaxon
pKa (Strongest Basic)-0.91Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count4Chemaxon
Polar Surface Area150.7 Å2Chemaxon
Rotatable Bond Count10Chemaxon
Refractivity138.2 m3·mol-1Chemaxon
Polarizability56.79 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.6781
Blood Brain Barrier-0.8805
Caco-2 permeable-0.6532
P-glycoprotein substrateSubstrate0.8394
P-glycoprotein inhibitor IInhibitor0.671
P-glycoprotein inhibitor IIInhibitor0.6377
Renal organic cation transporterNon-inhibitor0.8188
CYP450 2C9 substrateNon-substrate0.7965
CYP450 2D6 substrateNon-substrate0.7996
CYP450 3A4 substrateSubstrate0.621
CYP450 1A2 substrateNon-inhibitor0.7987
CYP450 2C9 inhibitorNon-inhibitor0.7265
CYP450 2D6 inhibitorNon-inhibitor0.87
CYP450 2C19 inhibitorNon-inhibitor0.6908
CYP450 3A4 inhibitorNon-inhibitor0.9659
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8434
Ames testNon AMES toxic0.662
CarcinogenicityNon-carcinogens0.8555
BiodegradationReady biodegradable0.5913
Rat acute toxicity2.6263 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9828
hERG inhibition (predictor II)Non-inhibitor0.7092
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-2003980000-6580e12b890f1fd0a775
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-4201920000-27f14c022bf7ebe80c89
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-9014500000-302ffd2873c288b540da
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0ac1-5117950000-14169be236ef42656758
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-000f-7239100000-9e29593f5796edac3760
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-9101000000-b57517ad04195e5ad79f
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-228.69115
predicted
DeepCCS 1.0 (2019)
[M+H]+230.58653
predicted
DeepCCS 1.0 (2019)
[M+Na]+236.34856
predicted
DeepCCS 1.0 (2019)

Targets

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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
References
  1. Ali A, Aydin C, Gildemeister R, Romano KP, Cao H, Ozen A, Soumana D, Newton A, Petropoulos CJ, Huang W, Schiffer CA: Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance. ACS Chem Biol. 2013 Jul 19;8(7):1469-78. doi: 10.1021/cb400100g. Epub 2013 May 1. [Article]

Enzymes

Kind
Protein
Organism
Humans
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
References
  1. Kiser JJ, Flexner C: Direct-acting antiviral agents for hepatitis C virus infection. Annu Rev Pharmacol Toxicol. 2013;53:427-49. doi: 10.1146/annurev-pharmtox-011112-140254. Epub 2012 Nov 5. [Article]
  2. Wilby KJ, Greanya ED, Ford JA, Yoshida EM, Partovi N: A review of drug interactions with boceprevir and telaprevir: implications for HIV and transplant patients. Ann Hepatol. 2012 Mar-Apr;11(2):179-85. [Article]
  3. Hulskotte EG, Feng HP, Xuan F, Gupta S, van Zutven MG, O'Mara E, Wagner JA, Butterton JR: Pharmacokinetic evaluation of the interaction between hepatitis C virus protease inhibitor boceprevir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and pravastatin. Antimicrob Agents Chemother. 2013 Jun;57(6):2582-8. doi: 10.1128/AAC.02347-12. Epub 2013 Mar 25. [Article]
  4. FDA Approved Drug Products: VICTRELIS (boceprevir) Capsules [Link]
  5. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  6. Boceprevir FDA label [File]
Kind
Protein
Organism
Humans
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
References
  1. Kiser JJ, Flexner C: Direct-acting antiviral agents for hepatitis C virus infection. Annu Rev Pharmacol Toxicol. 2013;53:427-49. doi: 10.1146/annurev-pharmtox-011112-140254. Epub 2012 Nov 5. [Article]
  2. Hulskotte E, Gupta S, Xuan F, van Zutven M, O'Mara E, Feng HP, Wagner J, Butterton J: Pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers. Hepatology. 2012 Nov;56(5):1622-30. doi: 10.1002/hep.25831. Epub 2012 Oct 14. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Based on the findings of in vitro studies, boceprevir has the potential to inhibit P-gp; however, it had limited p-glycoprotein inhibitory potential at clinically relevant concentrations in a drug interaction study.
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. Kiser JJ, Flexner C: Direct-acting antiviral agents for hepatitis C virus infection. Annu Rev Pharmacol Toxicol. 2013;53:427-49. doi: 10.1146/annurev-pharmtox-011112-140254. Epub 2012 Nov 5. [Article]

Drug created at May 12, 2013 04:45 / Updated at February 21, 2021 18:52