Vinflunine

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 .

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 .

Description

Vinflunine (also referred to as PM391) is a semisynthetic analog of the natural vinca alkaloids vinblastine and vincristine that was approved by the European Medicines Agency (EMEA) in 2009 for the treatment of adult patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen. Vinflunine is synthesized from anhydrovinblastine in a superacid media (HF-SbF₅) and in the presence of a chlorinated solvent like CHCl₃ or CCl₄.

Originator

Pierre Fabre (France)

Indications

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 .

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 . 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 .
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 .

Definition

ChEBI: An organic heteropentacyclic compound and an organic heterotetracyclic compound that is vinorelbine in which the tetrahydropyridine moiety of the heterotetracyclic part of the molecule has been redced to the corresponding piperidine, and in which the ethy group attached to this ring has been replaced by a 1,1-difluoroethyl group.

brand name

Javlor

Pharmacokinetics

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 .

Clinical Use

Antineoplastic agent (vinca alkaloid):
Treatment of advanced or metastatic bladder cancer

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: possible increased risk of ventricular arrhythmias with delamanid; concentration possibly reduced by rifampicin - avoid.
Antidepressants: concentration possibly reduced by St Johns wort - avoid.
Antifungals: concentration increased by ketoconazole and possibly itraconazole (increased risk of neurotoxicity) - avoid.
Antimalarials: avoid with piperaquine with artenimol.
Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).
Antivirals: concentration possibly increased by ritonavir - avoid.
Grapefruit juice: concentration of vinflunine increased - avoid.

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 .

Metabolism

Metabolised by the cytochrome CYP3A4 isoenzyme, except for 4-O-deacetylvinflunine (DVFL), the only active metabolite and main metabolite in blood which is formed by multiple esterases. Excretion occurs via the faeces (about two-thirds) and the urine (about one-third).