Identification
- Name
- Boceprevir
- Accession Number
- DB08873 (DB05665)
- Type
- Small Molecule
- Groups
- Approved, Withdrawn
- Description
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.
- Structure
Structure for Boceprevir (DB08873)
- Synonyms
- Boceprevir
- External IDs
- EBP 520 / EBP-520 / SCH 503034 / SCH-503034
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Unlock Additional DataVictrelis Capsule 200 mg Oral Merck Ltd. 2011-08-02 2017-01-10 Canada 
Victrelis Capsule 200 mg/1 Oral Merck Sharp & Dohme Limited 2011-05-13 2015-12-31 US 
Victrelis Capsule 200 mg Oral Merck Sharp & Dohme Limited 2011-07-18 2018-07-31 EU 
Victrelis Capsule 200 mg Oral Merck Sharp & Dohme Limited 2011-07-18 2018-07-31 EU Additional Data Available- Application NumberApplication Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
Learn more - Product CodeProduct Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Victrelis Triple Boceprevir (200 mg) + Peginterferon alfa-2b (100 mcg) + Ribavirin (200 mg) Capsule; Powder, for solution Oral; Subcutaneous Merck Ltd. 2011-08-16 2017-01-10 Canada Victrelis Triple Boceprevir (200 mg) + Peginterferon alfa-2b (80 mcg) + Ribavirin (200 mg) Capsule; Powder, for solution Oral; Subcutaneous Merck Ltd. 2011-08-16 2017-01-10 Canada Victrelis Triple Boceprevir (200 mg) + Peginterferon alfa-2b (150 mcg) + Ribavirin (200 mg) Capsule; Powder, for solution Oral; Subcutaneous Merck Ltd. 2011-08-16 2016-09-02 Canada Victrelis Triple Boceprevir (200 mg) + Peginterferon alfa-2b (120 mcg) + Ribavirin (200 mg) Capsule; Powder, for solution Oral; Subcutaneous Merck Ltd. 2011-08-16 2016-09-02 Canada - Categories
- Acids, Acyclic
- Amino Acids
- Amino Acids, Cyclic
- Amino Acids, Peptides, and Proteins
- Antiinfectives for Systemic Use
- Antiviral Agents
- Antivirals for Systemic Use
- Antivirals for treatment of HCV infections
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strong)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Inhibitors
- Cytochrome P-450 CYP3A5 Inhibitors (strong)
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Direct Acting Antivirals
- HCV NS3/4A Protease Inhibitors
- Imines
- Imino Acids
- NS3/4A Protease Inhibitors
- P-glycoprotein inhibitors
- Protease Inhibitors
- UNII
- 89BT58KELH
- CAS number
- 394730-60-0
- Weight
- Average: 519.6767
Monoisotopic: 519.342069575 - Chemical Formula
- C27H45N5O5
- 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
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.
- Associated Conditions
- 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.
Target Actions Organism ANS3/4A protein inhibitorHepatitis 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.
- 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.
- Affected organisms
- Hepatitis C Virus
- 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.
Drug Interaction Unlock Additional Data(R)-warfarin The serum concentration of Boceprevir can be increased when it is combined with (R)-warfarin. (S)-Warfarin The serum concentration of (S)-Warfarin can be increased when it is combined with Boceprevir. 4-hydroxycoumarin The metabolism of 4-hydroxycoumarin can be decreased when combined with Boceprevir. 9-aminocamptothecin The metabolism of 9-aminocamptothecin can be decreased when combined with Boceprevir. Abatacept The metabolism of Boceprevir can be increased when combined with Abatacept. Abemaciclib The metabolism of Abemaciclib can be decreased when combined with Boceprevir. Abiraterone The metabolism of Abiraterone can be decreased when combined with Boceprevir. Acalabrutinib The metabolism of Boceprevir can be decreased when combined with Acalabrutinib. Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Boceprevir. Adalimumab The metabolism of Boceprevir can be increased when combined with Adalimumab. Additional Data Available- Extended DescriptionExtended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
Learn more - Severity
- Evidence Level
- ActionAction
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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- Food Interactions
- Take with or without food. Food decreases drug exposure, but not to a clinically significant extent.
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
- 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. [PubMed:23140245]
- 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. [PubMed:22799589]
- 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. [PubMed:22506260]
- 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. [PubMed:16495264]
- 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]
- 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]
- 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
- 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
- ATC Codes
- J05AP03 — Boceprevir
- FDA label
- Download (403 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Capsule Oral 200 mg/1 Capsule Oral 200 mg Capsule; powder, for solution Oral; Subcutaneous - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Unlock Additional DataUS7772178 No 2010-08-10 2027-11-11 US US8119602 No 2012-02-21 2027-03-17 US USRE43298 No 2012-04-03 2022-02-22 US Additional Data Available- Filed On
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0234 mg/mL ALOGPS logP 1.93 ALOGPS logP 1.78 ChemAxon logS -4.4 ALOGPS pKa (Strongest Acidic) 12.44 ChemAxon pKa (Strongest Basic) -0.91 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 5 ChemAxon Hydrogen Donor Count 4 ChemAxon Polar Surface Area 150.7 Å2 ChemAxon Rotatable Bond Count 10 ChemAxon Refractivity 138.2 m3·mol-1 ChemAxon Polarizability 56.78 Å3 ChemAxon Number of Rings 3 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
Property Value Probability Human Intestinal Absorption + 0.6781 Blood Brain Barrier - 0.8805 Caco-2 permeable - 0.6532 P-glycoprotein substrate Substrate 0.8394 P-glycoprotein inhibitor I Inhibitor 0.671 P-glycoprotein inhibitor II Inhibitor 0.6377 Renal organic cation transporter Non-inhibitor 0.8188 CYP450 2C9 substrate Non-substrate 0.7965 CYP450 2D6 substrate Non-substrate 0.7996 CYP450 3A4 substrate Substrate 0.621 CYP450 1A2 substrate Non-inhibitor 0.7987 CYP450 2C9 inhibitor Non-inhibitor 0.7265 CYP450 2D6 inhibitor Non-inhibitor 0.87 CYP450 2C19 inhibitor Non-inhibitor 0.6908 CYP450 3A4 inhibitor Non-inhibitor 0.9659 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8434 Ames test Non AMES toxic 0.662 Carcinogenicity Non-carcinogens 0.8555 Biodegradation Ready biodegradable 0.5913 Rat acute toxicity 2.6263 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9828 hERG inhibition (predictor II) Non-inhibitor 0.7092
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Taxonomy
- 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
- Hybrid peptide / Alpha-dipeptide / N-carbamoyl-alpha-amino acid or derivatives / Valine or derivatives / Alpha-amino acid amide / Alpha-amino acid or derivatives / Piperidinecarboxamide / 2-piperidinecarboxamide / N-acyl-piperidine / Pyrrolidine carboxylic acid or derivatives show 25 more
- Molecular Framework
- Aliphatic heteropolycyclic compounds
- External Descriptors
- ureas, tripeptide (CHEBI:68621)
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
References
- 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. [PubMed:23594083]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- 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. [PubMed:23140245]
- 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. [PubMed:22345334]
- 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. [PubMed:23529734]
- FDA Approved Drug Products: VICTRELIS (boceprevir) Capsules [Link]
- FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
- Boceprevir FDA label [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- 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. [PubMed:23140245]
- 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. [PubMed:22576324]
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
- 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. [PubMed:23140245]
Drug created on May 11, 2013 22:45 / Updated on June 12, 2020 11:42
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