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

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Similar Structures

Structure for Vinflunine (DB11641)

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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

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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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Associated Conditions

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		••••••••••••	•••••	••••••• •• • ••••• ••••••••••••••••••• •••••••

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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	inhibitor	Humans

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.

Hover over products below to view reaction partners

• Vinflunine
  • 4-O-deacetylvinflunine

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

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	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.

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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
Javlor	Injection, solution, concentrate	25 mg/ml	Intravenous	Pierre Fabre Médicament	2016-09-08	Not applicable
Javlor	Injection, solution, concentrate	25 mg/ml	Intravenous	Pierre Fabre Médicament	2016-09-08	Not applicable
Javlor	Injection, solution, concentrate	25 mg/ml	Intravenous	Pierre Fabre Médicament	2016-09-08	Not applicable
Javlor	Injection, solution, concentrate	25 mg/ml	Intravenous	Pierre Fabre Médicament	2016-09-08	Not applicable

Categories

ATC Codes

L01CA05 — Vinflunine

• L01CA — Vinca alkaloids and analogues
• L01C — PLANT ALKALOIDS AND OTHER NATURAL PRODUCTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

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 / Heteroaromatic compounds / Pyrroles / Tertiary alcohols / Methyl esters / Amino acids and derivatives / Cyclic alcohols and derivatives / Trialkylamines / Azacyclic compounds / Carbonyl compounds / Hydrocarbon derivatives / Organic oxides / Alkyl fluorides / Organofluorides / Organopnictogen compounds

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Substituents

3-alkylindole / Alcohol / Alkyl aryl ether / Alkyl fluoride / Alkyl halide / Amine / Amino acid or derivatives / Anisole / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carbazole / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Catharanthine skeleton / Cyclic alcohol / Dialkylarylamine / Ether / Heteroaromatic compound / Hydrocarbon derivative / Indole / Indole or derivatives / Methyl ester / N-alkylpyrrolidine / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Piperidine / Pyrrole / Pyrrolidine / Tertiary alcohol / Tertiary aliphatic amine / Tertiary aliphatic/aromatic amine / Tertiary amine / Tricarboxylic acid or derivatives / Vinca alkaloid skeleton

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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

1. 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]
2. 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]
3. 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]
4. 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]
5. 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]
6. EMA: Vinflunine Public Assessment Report [Link]
7. 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

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

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-014i-0000000390-ab7ecb20523f8e8e121b
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0bt9-5000001910-9210368d0b7e8d45df88
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-05mk-0000009860-9a4db985f3a6e44d135a
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a4i-9000003000-5d4a3e27a8f2058b5b56
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0zfr-0109210210-32178f0b2a80cbe256ef
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0aov-9004007830-120887555724b28db405

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	282.49762	predicted	DeepCCS 1.0 (2019)
[M+H]+	284.22134	predicted	DeepCCS 1.0 (2019)
[M+Na]+	290.5506	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Tubulin beta chain

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

1. Rai SS, Wolff J: Localization of the vinblastine-binding site on beta-tubulin. J Biol Chem. 1996 Jun 21;271(25):14707-11. [Article]
2. 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]
3. 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]

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Drug created at October 17, 2016 21:30 / Updated at February 03, 2022 06:26