Vinflunine
Vinflunine Uses, Dosage, Side Effects, Food Interaction and all others data.
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 . 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 . 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 . 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 , there is currently no standard therapy in patients with advanced urothelial carcinoma . 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 . 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 .
The antitumour effects of vinflunine are dependent on concentration and exposure duration of the drug . Vinflunine mediates an anti-mitotic action by inhibiting the microtubule assembly at micromolar concentrations and reducing the rate and extent of microtubule growing events . 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 . Compared with other vinca alkaloids, vinflunine is a less-potent inductor of drug resistance in vitro .
| Trade Name | Vinflunine |
| Generic | Vinflunine |
| Vinflunine Other Names | Vinflunina, Vinflunine, Vinfluninum |
| Type | |
| Formula | C45H54F2N4O8 |
| Weight | Average: 816.944 Monoisotopic: 816.390971041 |
| 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. . Binding to alpha-1 acid glycoprotein and to platelets is negligible (< 5%) . |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
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.
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 .
Vinflunine is also used to associated treatment for these conditions: Transitional Cell Carcinoma of the Urothelial Tract, Metastatic Transitional Cell Carcinoma of the Urothelial Tract
How Vinflunine works
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 . 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 . 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 . 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 . 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 . Via direct binding to tubulin, vinflunine inhibits microtubule polymerization and induces a G2+M arrest, or a mitotic arrest . Vinflunine disrupts the dynamic function of microtubules by suppressing treadmilling and slowing the microtubule growth rate while increasing growth duration . Ultimately, mitotic accumulation at the metaphase/anaphase transition results in cell apoptosis .
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 . The severity of correlates with the AUC of, or overall exposure to, vinflunine .
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 . 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 .
Food Interaction
- 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.
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 .
Elimination Route
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 .
Half Life
The mean terminal half-life is approximately 40 h . The half life of the main metabolite, DVFL, is approximately 120 hours .
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 .
Elimination Route
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 .
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