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Approved, Withdrawn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
Thumb
Synonyms
Not Available
External IDs
EBP 520 / EBP-520 / SCH 503034 / SCH-503034
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VictrelisCapsule200 mgOralMerck Ltd.2011-08-022017-01-10Canada
VictrelisCapsule200 mg/1OralMerck Sharp & Dohme Limited2011-05-132015-12-31Us
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Victrelis TripleBoceprevir (200 mg) + Peginterferon alfa-2b (100 mcg) + Ribavirin (200 mg)Capsule; Powder, for solutionOral; SubcutaneousMerck Ltd.2011-08-162017-01-10Canada
Victrelis TripleBoceprevir (200 mg) + Peginterferon alfa-2b (120 mcg) + Ribavirin (200 mg)Capsule; Powder, for solutionOral; SubcutaneousMerck Ltd.2011-08-162016-09-02Canada
Victrelis TripleBoceprevir (200 mg) + Peginterferon alfa-2b (80 mcg) + Ribavirin (200 mg)Capsule; Powder, for solutionOral; SubcutaneousMerck Ltd.2011-08-162017-01-10Canada
Victrelis TripleBoceprevir (200 mg) + Peginterferon alfa-2b (150 mcg) + Ribavirin (200 mg)Capsule; Powder, for solutionOral; SubcutaneousMerck Ltd.2011-08-162016-09-02Canada
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
VictrelisBoceprevir (200 mg)CapsuleOralMerck Sharp & Dohme Limited2011-07-182018-07-31Eu
VictrelisBoceprevir (200 mg)CapsuleOralMerck Sharp & Dohme Limited2011-07-182018-07-31Eu
Categories
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.

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].

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
DrugInteraction
(1S,6R)-3-{[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRAZIN-7(8H)-YL]CARBONYL}-6-(2,4,5-TRIFLUOROPHENYL)CYCLOHEX-3-EN-1-AMINEThe serum concentration of (1S,6R)-3-{[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRAZIN-7(8H)-YL]CARBONYL}-6-(2,4,5-TRIFLUOROPHENYL)CYCLOHEX-3-EN-1-AMINE can be decreased when it is combined with Boceprevir.
1,10-PhenanthrolineThe serum concentration of 1,10-Phenanthroline can be decreased when it is combined with Boceprevir.
16-BromoepiandrosteroneThe serum concentration of 16-Bromoepiandrosterone can be increased when it is combined with Boceprevir.
19-norandrostenedioneThe serum concentration of 19-norandrostenedione can be increased when it is combined with Boceprevir.
3,4-DichloroisocoumarinThe serum concentration of 3,4-Dichloroisocoumarin can be decreased when it is combined with Boceprevir.
4-(2-Aminoethyl)Benzenesulfonyl FluorideThe serum concentration of 4-(2-Aminoethyl)Benzenesulfonyl Fluoride can be decreased when it is combined with Boceprevir.
5-androstenedioneThe serum concentration of 5-androstenedione can be increased when it is combined with Boceprevir.
AbacavirThe serum concentration of Abacavir can be decreased when it is combined with Boceprevir.
AbemaciclibThe risk or severity of adverse effects can be increased when Boceprevir is combined with Abemaciclib.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Boceprevir.
Food Interactions
  • Food increases the exposure of boceprevir by up to 65%. However, bioavailability is not affected and thus can be taken without regards to meals.

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. [PubMed:23140245]
  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. [PubMed:22799589]
  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. [PubMed:22506260]
  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. [PubMed:16495264]
  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. [PubMed:28497432]
  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. [PubMed:25585348]
  7. 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
ChEBI
68621
ChEMBL
CHEMBL218394
PharmGKB
PA165948902
HET
HU5
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Boceprevir
ATC Codes
J05AE12 — Boceprevir
FDA label
Download (403 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedTreatmentTransplantation, Liver1
1CompletedNot AvailableGastric Acid-related Disorders / HCV Infections1
1CompletedBasic ScienceHealthy Volunteers2
1CompletedOtherHuman Immunodeficiency Virus (HIV) Infections1
1CompletedOtherThrombocytopenias1
1CompletedPreventionHepatitis C Viral Infection1
1CompletedTreatmentHCV Infections / Human Immunodeficiency Virus (HIV) Infections1
1CompletedTreatmentHepatitis C Viral Infection2
1CompletedTreatmentHepatitis C Virus (HCV)1
1TerminatedTreatmentChronic Hepatitis C Virus (HCV) Infection1
2CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection4
2CompletedTreatmentHCV Infections / Hepatitis C Viral Infection / Human Immunodeficiency Virus (HIV) Infections1
2CompletedTreatmentHCV Infections / Liver Cirrhosis, Experimental1
2CompletedTreatmentHepatitis C Viral Infection / Human Immunodeficiency Virus (HIV)1
2, 3TerminatedOtherChronic Hepatitis C Virus (HCV) Infection / Hepacivirus1
3CompletedTreatmentChronic Hepatitis C Genotype 11
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection8
3CompletedTreatmentCoinfection / Hepatitis C Viral Infection / Human Immunodeficiency Virus (HIV) Infections1
3CompletedTreatmentHepatitis C Viral Infection1
3CompletedTreatmentHepatitis C Viral Infection / Human Immunodeficiency Virus (HIV) Infections1
3TerminatedTreatmentHepatitis C Viral Infection / Liver Diseases1
3Unknown StatusTreatmentGenotype 4 Chronic Hepatitis C Infection1
3Unknown StatusTreatmentLate Complication From Liver Transplant1
3WithdrawnTreatmentChronic Hepatitis C Virus (HCV) Infection2
3WithdrawnTreatmentHepatitis C Viral Infection1
4CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection1
4CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Human Immunodeficiency Virus (HIV)1
4CompletedTreatmentHepatitis C Viral Infection1
4TerminatedTreatmentHepatitis / Human Immunodeficiency Virus Infection(HIV)/Acquired Immunodeficiency Syndrome (AIDS)1
4Unknown StatusTreatmentChronic Hepatitis C Virus (HCV) Infection / End Stage Renal Disease (ESRD)1
4WithdrawnTreatmentHepatitis C Viral Infection1
Not AvailableCompletedNot AvailableChronic Hepatitis C Virus (HCV) Infection1
Not AvailableCompletedNot AvailableHepatitis C Viral Infection / Human Immunodeficiency Virus (HIV)1
Not AvailableCompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Hepatitis C Viral Infection / Liver Cirrhosis1
Not AvailableRecruitingNot AvailableChronic Hepatitis C Virus (HCV) Infection1
Not AvailableRecruitingNot AvailableChronic Hepatitis C Virus (HCV) Infection / Human Immunodeficiency Virus (HIV)1
Not AvailableTerminatedNot AvailableChronic Hepatitis C Virus (HCV) Infection1
Not AvailableTerminatedNot AvailableHepatitis C Infection1
Not AvailableWithdrawnTreatmentEnd Stage Renal Disease (ESRD) / Hepatitis C Infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral200 mg
CapsuleOral200 mg/1
Capsule; powder, for solutionOral; Subcutaneous
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7772178No2007-11-112027-11-11Us
US8119602No2007-03-172027-03-17Us
USRE43298No2002-02-222022-02-22Us

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
Polarizability56.78 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/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 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
  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. [PubMed:23594083]

Enzymes

Kind
Protein
Organism
Human
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. [PubMed:23140245]
  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. [PubMed:22345334]
Kind
Protein
Organism
Human
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. [PubMed:23140245]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
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. 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 October 01, 2018 14:43