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General Description:

Vinflunine, identified by CAS number 162652-95-1, is a notable compound with significant therapeutic applications. 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 , , and . 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 .

Indications:

This drug is primarily indicated for: 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 . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Vinflunine undergoes metabolic processing primarily in: 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 . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Vinflunine are crucial for its therapeutic efficacy: 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 . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Vinflunine is an important consideration for its dosing schedule: The mean terminal half-life is approximately 40 h . The half life of the main metabolite, DVFL, is approximately 120 hours . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Vinflunine exhibits a strong affinity for binding with plasma proteins: 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%) . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Vinflunine from the body primarily occurs through: 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 . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Vinflunine is distributed throughout the body with a volume of distribution of: 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 . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Vinflunine is a critical factor in determining its safe and effective dosage: 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 . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Vinflunine exerts its therapeutic effects through: 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_ . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Vinflunine functions by: 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 . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Vinflunine 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, classified under the direct parent group Vinca alkaloids. This compound is a part of the Organic compounds, falling under the Alkaloids and derivatives superclass, and categorized within the Vinca alkaloids class, specifically within the None subclass.

Categories:

Vinflunine is categorized under the following therapeutic classes: 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. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Vinflunine include:

• Melting Point: 244