Identification

Name
Vinflunine
Accession Number
DB11641
Type
Small Molecule
Groups
Approved, Investigational
Description

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 [5]. 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 [5]. In murine tumors and human tumor xenografts, vinflunine exhibits an antitumor efficacy than Vinorelbine, Vinblastine, and Vincristine [A31975].

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 [5], 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].

Structure
Thumb
Synonyms
  • 20',20'-difluoro-3',4'-dihydrovinorelbine
  • 4'-deoxy-20',20'-difluoro-5'-norvincaleukoblastine
  • 4'-deoxy-20',20'-difluoro-8'-norvincaleukoblastine
  • Vinflunina
  • Vinflunine
  • Vinfluninum
Product Ingredients
IngredientUNIICASInChI Key
Vinflunine ditartrate33MG53C7XW194468-36-5TXONSEMUKVZUON-WVJCOWEJSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
JavlorInjection, solution, concentrate25 mg/mlIntravenousPierre Fabre Médicament2009-09-21Not applicableEu
JavlorInjection, solution, concentrate25 mg/mlIntravenousPierre Fabre Médicament2009-09-21Not applicableEu
JavlorInjection, solution, concentrate25 mg/mlIntravenousPierre Fabre Médicament2009-09-21Not applicableEu
JavlorInjection, solution, concentrate25 mg/mlIntravenousPierre Fabre Médicament2009-09-21Not applicableEu
JavlorInjection, solution, concentrate25 mg/mlIntravenousPierre Fabre Médicament2009-09-21Not applicableEu
JavlorInjection, solution, concentrate25 mg/mlIntravenousPierre Fabre Médicament2009-09-21Not applicableEu
JavlorInjection, solution, concentrate25 mg/mlIntravenousPierre Fabre Médicament2009-09-21Not applicableEu
JavlorInjection, solution, concentrate25 mg/mlIntravenousPierre Fabre Médicament2009-09-21Not applicableEu
JavlorInjection, solution, concentrate25 mg/mlIntravenousPierre Fabre Médicament2009-09-21Not applicableEu
JavlorInjection, solution, concentrate25 mg/mlIntravenousPierre Fabre Médicament2009-09-21Not applicableEu
Categories
UNII
5BF646324K
CAS number
162652-95-1
Weight
Average: 816.944
Monoisotopic: 816.390971041
Chemical Formula
C45H54F2N4O8
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

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 [6].

Associated Conditions
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 [5]. 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].

TargetActionsOrganism
ATubulin beta chain
inhibitor
Human
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 [6].

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 [6].

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. [6]. Binding to alpha-1 acid glycoprotein and to platelets is negligible (< 5%) [6].

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 [6].

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 [6].

Half life

The mean terminal half-life is approximately 40 h [6]. The half life of the main metabolite, DVFL, is approximately 120 hours [6].

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 [6].

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 [6]. The severity of correlates with the AUC of, or overall exposure to, vinflunine [6].

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 [6]. 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 [6].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenThe serum concentration of Vinflunine can be increased when it is combined with Acetaminophen.
AcetazolamideThe metabolism of Vinflunine can be decreased when combined with Acetazolamide.
Acetyl sulfisoxazoleThe metabolism of Vinflunine can be decreased when combined with Acetyl sulfisoxazole.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Vinflunine.
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Vinflunine.
AlbendazoleThe serum concentration of Vinflunine can be increased when it is combined with Albendazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Vinflunine.
AlfentanilThe metabolism of Alfentanil can be decreased when combined with Vinflunine.
AlfuzosinThe metabolism of Vinflunine can be decreased when combined with Alfuzosin.
AlmotriptanThe metabolism of Vinflunine can be decreased when combined with Almotriptan.
Food Interactions
Not Available

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. [PubMed:9515574]
  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. [PubMed:11016627]
  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. [PubMed:28042310]
  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. [PubMed:18538179]
  5. EMA: Vinflunine Public Assessment Report [Link]
  6. EMA Label (SUMMARY OF PRODUCT CHARACTERISTICS): Javlor [Link]
External Links
ChemSpider
8804619
ChEBI
90241
ChEMBL
CHEMBL2110725
Wikipedia
Vinflunine
ATC Codes
L01CA05 — Vinflunine
MSDS
Download (49.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentBladder Cancers / Renal Pelvis Cancer / Transitional Cell Carcinoma / Ureteral Cancer / Urethral Cancer1
1CompletedTreatmentCancers2
1CompletedTreatmentUnspecified Adult Solid Tumor, Protocol Specific1
1WithdrawnTreatmentCancers1
1, 2CompletedTreatmentAdvanced Urothelial Cancer of Bladder After Failure of Platinum-containing Therapy1
1, 2WithdrawnTreatmentBladder Cancers1
2Active Not RecruitingTreatmentBladder Cancers / Renal Pelvis Cancer / Transitional Cell Carcinoma / Ureteral Cancer / Urethral Cancer1
2Active Not RecruitingTreatmentLocally-advanced or Metastatic Penile Neoplasms1
2CompletedTreatmentBladder Cancers / Neoplasm, Bladder / Neoplasms, Kidney / Transitional Cell Carcinoma / Ureter Neoplasms1
2CompletedTreatmentBladder Transitional Cell Carcinoma Stage IV1
2CompletedTreatmentCancer, Breast / Neoplasms, Breast1
2CompletedTreatmentCarcinoma, Small Cell / Lung Cancers1
2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2CompletedTreatmentProstate Cancer1
2CompletedTreatmentTransitional Cell Carcinoma1
2TerminatedTreatmentLung Cancers1
2WithdrawnTreatmentCancer, Breast1
2, 3CompletedTreatmentBladder Cancers / Metastasis / Transitional Cell Carcinoma1
2, 3TerminatedTreatmentMalignant Neoplasm of Stomach1
2, 3Unknown StatusTreatmentUrothelium Transitional Cell Carcinoma1
3Active Not RecruitingTreatmentBladder Cancers1
3Active Not RecruitingTreatmentRecurrent or Metastatic Head and Neck Carcinoma1
3Active Not RecruitingTreatmentUrothelial Cancer1
3CompletedTreatmentBladder Cancers / Neoplasm, Bladder / Transitional Cell Carcinoma of the Urothelial Tract1
3CompletedTreatmentCancer, Breast / Metastases1
3CompletedTreatmentMalignant Neoplasm of Breast1
3RecruitingTreatmentBladder Cancers / Ureteral Cancer / Urothelial Cancer1
3RecruitingTreatmentUrothelial Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solution, concentrateIntravenous25 mg/ml
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)244MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.00564 mg/mLALOGPS
logP4.5ALOGPS
logP4.65ChemAxon
logS-5.2ALOGPS
pKa (Strongest Acidic)10.87ChemAxon
pKa (Strongest Basic)8.66ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area133.87 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity216.53 m3·mol-1ChemAxon
Polarizability85.68 Å3ChemAxon
Number of Rings9ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

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 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
Vinca alkaloid skeleton / Catharanthine skeleton / Carbazole / 3-alkylindole / Indole / Indole or derivatives / Tricarboxylic acid or derivatives / Anisole / Dialkylarylamine / Tertiary aliphatic/aromatic amine
show 34 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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. [PubMed:8663038]
  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. [PubMed:19455242]
  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. [PubMed:28042310]

Enzymes

Kind
Protein
Organism
Human
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
Human
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
2. High density lipoprotein
Kind
Protein group
Organism
Human
Pharmacological action
No
Actions
Substrate
Kind
Protein group
Organism
Human
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
Human
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
  1. 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. [PubMed:9740539]
Kind
Protein
Organism
Human
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 on October 17, 2016 15:30 / Updated on October 01, 2018 16:55