Vinflunine
Identification
- Summary
Vinflunine is a vinca alkaloid used to treat advanced or metastatic transitional cell carcinoma of the urothelial tract after a platinum containing treatment has failed.
- Brand Names
- Javlor
- Generic Name
- Vinflunine
- DrugBank Accession Number
- DB11641
- Background
Vinflunine is a third-generation member of the vinca alkaloid family with anti-tumour actions. It was first described in 1998 at the Pierre Fabre research center in France. Like other vinca agents, vinflunine is an anti-mitotic agent that induces a cell cycle arrest at the G2/M phase and promotes cell death via apoptosis 6. Vinflunine is a microtubule inhibitor that binds to tubulin at or near to the vinca binding sites to inhibits its polymerization into microtubules during cell proliferation 6. In murine tumors and human tumor xenografts, vinflunine exhibits an antitumor efficacy than Vinorelbine, Vinblastine, and Vincristine 5.
Having an incidence of 429,700 new cases per year worldwide, urothelial carcinoma of the bladder is one of the most common malignancies that mostly affects individuals aged 50–79 years 3. Some patients with advanced urothelial carcinoma experience inadequate therapeutic response from a prior platinum-containing regimen. While these patients have a median survival of approximately 4 months and a poor prognosis 6, there is currently no standard therapy in patients with advanced urothelial carcinoma 3. In 2009, vinflunine was approved by the European Medicines Agency (EMA) as a second-line therapy of metastatic and advanced urothelial cancer after failure of platinum-based treatment 3. Vinflunine ditartrate is an active ingredient in the EMA-authorised product Javlor for intravenous infusion. Efficacy and safety of vinflunine has not been studied in patients with performance status of 2 or less. The clinical use of vinflunine in other urologic malignancies, such as inoperable cancer of the penis, are currently have been investigated 3.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 816.944
Monoisotopic: 816.390971041 - Chemical Formula
- C45H54F2N4O8
- Synonyms
- 20',20'-difluoro-3',4'-dihydrovinorelbine
- 4'-deoxy-20',20'-difluoro-5'-norvincaleukoblastine
- 4'-deoxy-20',20'-difluoro-8'-norvincaleukoblastine
- Vinflunina
- Vinflunine
- Vinfluninum
Pharmacology
- Indication
For use as a monotherapy in adults with advanced or transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing therapy 7.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Transitional cell carcinoma of the urothelial tract •••••••••••• ••••• ••••••• •• • ••••• ••••••••••••••••••• ••••••• Treatment of Transitional cell carcinoma metastatic of the urothelial tract •••••••••••• ••••• ••••••• •• • ••••• ••••••••••••••••••• ••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
The antitumour effects of vinflunine are dependent on concentration and exposure duration of the drug 1. Vinflunine mediates an anti-mitotic action by inhibiting the microtubule assembly at micromolar concentrations and reducing the rate and extent of microtubule growing events 1. In vivo, vinflunine displays a significant antitumor activity against a broad spectrum of human xenografts in mice both in terms of survival prolongation and tumour growth inhibition 6. Compared with other vinca alkaloids, vinflunine is a less-potent inductor of drug resistance in vitro 3.
- Mechanism of action
Microtubules are a major component of the cytoskeleton that have a critical role in maintenance of cell shape, mobility, adhesion and intracellular integrity. They also play a role in the formation of the mitotic spindle and chromosomal segregation to the daughter cells at mitosis 4. Via GTP hydrolysis at the β-tubulin subunit and polymerization of tubulin into linear polymers, microtubules, or macromolecular filaments composed of tubulin heterodimers, are formed via a mechanism of nucleation-elongation 4. At the onset of mitosis, the interphase microtubule network disassembles into the tubulin. The tubulin reassembles into a new population of mitotic spindle microtubules that further undergo rapid successions of lengthening and shortening until they are attached to the newly duplicated sister chromatids at their centromeres 4. The dynamic behaviour of microtubules are characterized by two mechanical process: dynamic instability indicating repeated switches of growth and shortening at the ends, and microtubule treadmilling that involves the fast-growing (+) end of the microtubule accompanied by a net loss of the opposite slow-growing (-) end 4. Microtubule treadmilling plays a critical role in mitosis by generating the forces for separation of the chromosomes in the mitotic spindle from centrosome and kinetochores.
In both cancer and normal cells, vinflunine binds to tubulin at or near to the vinca binding sites at β-tubulin. It is proposed that in similarity to other vinca alkaloids, vinflunine is most likely to bind to β-tubulin subunit at the interdimer interface 4. Via direct binding to tubulin, vinflunine inhibits microtubule polymerization and induces a G2+M arrest, or a mitotic arrest 3. Vinflunine disrupts the dynamic function of microtubules by suppressing treadmilling and slowing the microtubule growth rate while increasing growth duration 2. Ultimately, mitotic accumulation at the metaphase/anaphase transition results in cell apoptosis 3.
Target Actions Organism ATubulin beta chain inhibitorHumans - Absorption
Vinflunine displays a linear pharmacokinetic profile in the range of administered doses (from 30 mg/m^2 to 400 mg/m^2) in cancer patients 7.
- Volume of distribution
The terminal volume of distribution is large, 2422 ± 676 L (about 35 l/kg), suggesting extensive distribution into tissues. The ratio between plasma and whole blood concentrations of 0.80 ± 0.12 7.
- Protein binding
Vinflunine is 67.2 ± 1.1% bound to human plasma proteins. It mainly binds to high density lipoproteins and serum albumin, and is non-saturable on the range of vinflunine concentrations observed in patients. 7. Binding to alpha-1 acid glycoprotein and to platelets is negligible (< 5%) 7.
- Metabolism
The metabolites of influnine are mostly cytochrome P450 3A4, but 4-O-deacetylvinflunine (DVFL) may be slowly formed by multiple esterases. DVFL is the main metabolite and is the only metabolite that retains pharmacological activity 7.
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- Route of elimination
Fecal excretion accounts for 2/3 of the total elimination of vinflunine and its metabolites and the remaining 1/3 of their elimination indicates urinary excretion 7.
- Half-life
The mean terminal half-life is approximately 40 h 7. The half life of the main metabolite, DVFL, is approximately 120 hours 7.
- Clearance
The total blood clearance was 40 L/h according to a population pharmacokinetic analysis in 372 patients. The inter- and intra-individual variability was low, with the coefficient of variation approximately 25% and 8%, respectively 7.
- Adverse Effects
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- Toxicity
Overdose of vinflunine is associated with bone marrow suppression with a risk of severe infection. There is no known antidote for vinflunine overdose. In case of overdose, the vital functions of the patient should be closely monitored and other appropriate measures, such as blood transfusions and administration of antibiotics or growth factors, should be taken if necessary 7. The severity of correlates with the AUC of, or overall exposure to, vinflunine 7.
In the in vivo micronucleus test in rat, vinflunine was clastogenic that induced chromosome breakage. In a mouse lymphoma assay, vinflunine displayed mutagenic and clastogenic potential without any metabolic activation 7. In the reproduction studies, vinflunine caused embryolethal and teratogenic effects in rabbits and teratogenic effects in rats. 2 cases of malformations of the uterus and vagina following vinflunine treatment were reported during the pre- and post-natal development study in rat 7.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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 Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Vinflunine can be increased when it is combined with Abametapir. Abatacept The metabolism of Vinflunine can be increased when combined with Abatacept. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Vinflunine. Abrocitinib The serum concentration of Vinflunine can be increased when it is combined with Abrocitinib. Acalabrutinib The metabolism of Vinflunine can be decreased when combined with Acalabrutinib. - Food Interactions
- Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of vinflunine.
- Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of vinflunine.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Vinflunine ditartrate 33MG53C7XW 194468-36-5 TXONSEMUKVZUON-WVJCOWEJSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Javlor Injection, solution, concentrate 25 mg/ml Intravenous Pierre Fabre Médicament 2016-09-08 Not applicable EU Javlor Injection, solution, concentrate 25 mg/ml Intravenous Pierre Fabre Médicament 2016-09-08 Not applicable EU Javlor Injection, solution, concentrate 25 mg/ml Intravenous Pierre Fabre Médicament 2016-09-08 Not applicable EU Javlor Injection, solution, concentrate 25 mg/ml Intravenous Pierre Fabre Médicament 2016-09-08 Not applicable EU Javlor Injection, solution, concentrate 25 mg/ml Intravenous Pierre Fabre Médicament 2016-09-08 Not applicable EU
Categories
- ATC Codes
- L01CA05 — Vinflunine
- Drug Categories
- Alkaloids
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Substrates
- Heterocyclic Compounds, Fused-Ring
- Indole Alkaloids
- Indoles
- Indolizidines
- Indolizines
- Narrow Therapeutic Index Drugs
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Secologanin Tryptamine Alkaloids
- Vinca Alkaloids
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as vinca alkaloids. These are alkaloids with a dimeric chemical structure composed of an indole nucleus (catharanthine), and a dihydroindole nucleus (vindoline), joined together.
- Kingdom
- Organic compounds
- Super Class
- Alkaloids and derivatives
- Class
- Vinca alkaloids
- Sub Class
- Not Available
- Direct Parent
- Vinca alkaloids
- Alternative Parents
- Ibogan-type alkaloids / Carbazoles / 3-alkylindoles / Tricarboxylic acids and derivatives / Dialkylarylamines / Anisoles / Aralkylamines / Alkyl aryl ethers / Piperidines / N-alkylpyrrolidines show 14 more
- Substituents
- 3-alkylindole / Alcohol / Alkyl aryl ether / Alkyl fluoride / Alkyl halide / Amine / Amino acid or derivatives / Anisole / Aralkylamine / Aromatic heteropolycyclic compound show 34 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 5BF646324K
- CAS number
- 162652-95-1
- InChI Key
- NMDYYWFGPIMTKO-KLCPSUAYSA-N
- InChI
- InChI=1S/C45H54F2N4O8/c1-8-42-14-11-16-51-17-15-43(36(42)51)30-19-31(34(56-5)20-33(30)49(4)37(43)45(55,40(54)58-7)38(42)59-25(2)52)44(39(53)57-6)21-26-18-27(41(3,46)47)23-50(22-26)24-29-28-12-9-10-13-32(28)48-35(29)44/h9-14,19-20,26-27,36-38,48,55H,8,15-18,21-24H2,1-7H3/t26-,27+,36-,37+,38+,42+,43+,44-,45-/m0/s1
- IUPAC Name
- methyl (1R,9R,10S,11R,12R,19R)-11-(acetyloxy)-4-[(1R,12S,14S,16R)-16-(1,1-difluoroethyl)-12-(methoxycarbonyl)-1,10-diazatetracyclo[12.3.1.0^{3,11}.0^{4,9}]octadeca-3(11),4,6,8-tetraen-12-yl]-12-ethyl-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.0^{1,9}.0^{2,7}.0^{16,19}]nonadeca-2,4,6,13-tetraene-10-carboxylate
- SMILES
- CC[C@@]12C=CCN3CC[C@@]4([C@H]13)[C@@H](N(C)C1=CC(OC)=C(C=C41)[C@]1(C[C@@H]3C[C@H](C[N@@](C3)CC3=C1NC1=CC=CC=C31)C(C)(F)F)C(=O)OC)[C@](O)([C@@H]2OC(C)=O)C(=O)OC
References
- Synthesis Reference
Fahy J, Hellier P, Breillout F, Bailly C. Vinflunine: discovery and synthesis of a novel microtubule inhibitor. Semin Oncol. 2008;35(3 Suppl 3):S3-5.
- General References
- Kruczynski A, Barret JM, Etievant C, Colpaert F, Fahy J, Hill BT: Antimitotic and tubulin-interacting properties of vinflunine, a novel fluorinated Vinca alkaloid. Biochem Pharmacol. 1998 Mar 1;55(5):635-48. [Article]
- Ngan VK, Bellman K, Panda D, Hill BT, Jordan MA, Wilson L: Novel actions of the antitumor drugs vinflunine and vinorelbine on microtubules. Cancer Res. 2000 Sep 15;60(18):5045-51. [Article]
- Gerullis H, Wawroschek F, Kohne CH, Ecke TH: Vinflunine in the treatment of advanced urothelial cancer: clinical evidence and experience. Ther Adv Urol. 2017 Jan;9(1):28-35. doi: 10.1177/1756287216677903. Epub 2016 Nov 21. [Article]
- Jordan MA, Horwitz SB, Lobert S, Correia JJ: Exploring the mechanisms of action of the novel microtubule inhibitor vinflunine. Semin Oncol. 2008 Jun;35(3 Suppl 3):S6-S12. doi: 10.1053/j.seminoncol.2008.01.009. [Article]
- Ngan VK, Bellman K, Hill BT, Wilson L, Jordan MA: Mechanism of mitotic block and inhibition of cell proliferation by the semisynthetic Vinca alkaloids vinorelbine and its newer derivative vinflunine. Mol Pharmacol. 2001 Jul;60(1):225-32. [Article]
- EMA: Vinflunine Public Assessment Report [Link]
- EMA Label (SUMMARY OF PRODUCT CHARACTERISTICS): Javlor [Link]
- External Links
- ChemSpider
- 8804619
- ChEBI
- 90241
- ChEMBL
- CHEMBL2110725
- ZINC
- ZINC000085537078
- Wikipedia
- Vinflunine
- MSDS
- Download (49.8 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Bladder Cancer / Ureteral Cancer / Urothelial Cancer 1 3 Active Not Recruiting Treatment Locally Advanced or Metastatic Unresectable Urothelial Cancer 1 3 Active Not Recruiting Treatment Urothelial Cancer 1 3 Completed Treatment Bladder Cancer 1 3 Completed Treatment Bladder Cancer / Bladder Neoplasm / Transitional Cell Carcinoma of the Urothelial Tract 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution, concentrate Intravenous 25 MG/ML Injection Parenteral 250 mg/10ml Injection Parenteral Solution Intravenous 25 mg/mL - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 244 MSDS - Predicted Properties
Property Value Source Water Solubility 0.00564 mg/mL ALOGPS logP 4.5 ALOGPS logP 4.65 Chemaxon logS -5.2 ALOGPS pKa (Strongest Acidic) 10.87 Chemaxon pKa (Strongest Basic) 8.66 Chemaxon Physiological Charge 2 Chemaxon Hydrogen Acceptor Count 8 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 133.87 Å2 Chemaxon Rotatable Bond Count 10 Chemaxon Refractivity 216.53 m3·mol-1 Chemaxon Polarizability 85.68 Å3 Chemaxon Number of Rings 9 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
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 282.49762 predictedDeepCCS 1.0 (2019) [M+H]+ 284.22134 predictedDeepCCS 1.0 (2019) [M+Na]+ 290.5506 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Ubiquitin protein ligase binding
- Specific Function
- Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain.
- Gene Name
- TUBB
- Uniprot ID
- P07437
- Uniprot Name
- Tubulin beta chain
- Molecular Weight
- 49670.515 Da
References
- Rai SS, Wolff J: Localization of the vinblastine-binding site on beta-tubulin. J Biol Chem. 1996 Jun 21;271(25):14707-11. [Article]
- Huzil JT, Chen K, Kurgan L, Tuszynski JA: The roles of beta-tubulin mutations and isotype expression in acquired drug resistance. Cancer Inform. 2007 Apr 27;3:159-81. [Article]
- Gerullis H, Wawroschek F, Kohne CH, Ecke TH: Vinflunine in the treatment of advanced urothelial cancer: clinical evidence and experience. Ther Adv Urol. 2017 Jan;9(1):28-35. doi: 10.1177/1756287216677903. Epub 2016 Nov 21. [Article]
Enzymes
- 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
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Toxic substance binding
- Specific Function
- Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Serum albumin
- Molecular Weight
- 69365.94 Da
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Not Available
- Specific Function
- Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Components:
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Efflux transmembrane transporter activity
- Specific Function
- Drug efflux transporter present in a number of stem cells that acts as a regulator of cellular differentiation. Able to mediate efflux from cells of the rhodamine dye and of the therapeutic drug do...
- Gene Name
- ABCB5
- Uniprot ID
- Q2M3G0
- Uniprot Name
- ATP-binding cassette sub-family B member 5
- Molecular Weight
- 138639.48 Da
References
- Etievant C, Barret JM, Kruczynski A, Perrin D, Hill BT: Vinflunine (20',20'-difluoro-3',4'-dihydrovinorelbine), a novel Vinca alkaloid, which participates in P-glycoprotein (Pgp)-mediated multidrug resistance in vivo and in vitro. Invest New Drugs. 1998;16(1):3-17. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
Drug created at October 17, 2016 21:30 / Updated at February 03, 2022 06:26