Chemical formula: C₄₅H₅₄F₂N₄O₈ Molecular mass: 816.944 g/mol
Vinflunine binds to tubulin at or near to the vinca binding sites inhibiting its polymerisation into microtubules, which results in treadmilling suppression, disruption of microtubule dynamic, mitotic arrest and apoptosis. In vivo, vinflunine displays significant antitumor activity against a broad spectrum of human xenografts in mice both in terms of survival prolongation and tumour growth inhibition.
Vinflunine pharmacokinetics is linear in the range of administered doses (from 30 mg/m² to 400 mg/m²) in cancer patients.
Blood exposure to vinflunine (AUC), significantly correlated with severity of leucopenia, neutropenia and fatigue.
Vinflunine is moderately bound to human plasma proteins (67.2±1.1%) with a ratio between plasma and whole blood concentrations of 0.80±0.12. Protein binding mainly involves 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%).
The terminal volume of distribution is large, 2422±676 litres (about 35 l/kg) suggesting extensive distribution into tissues.
All metabolites identified are formed 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.
Vinflunine is eliminated following a multi-exponential concentration decay, with a terminal half-life (t1/2) close to 40 h. DVFL is slowly formed and more slowly eliminated than vinflunine (t1/2 of approximately 120 h).
The excretion of vinflunine and its metabolites occurs through faeces (⅔) and urine (⅓). In a population pharmacokinetic analysis in 372 patients (656 pharmacokinetic profiles), the total blood clearance was 40 l/h with low inter and intra-individual variability (25% and 8%, respectively, expressed as coefficient of variation).
No modification of vinflunine and DVFL pharmacokinetics was observed in 25 patients presenting varying degrees of hepatic impairment, compared to patients with normal hepatic function. This was further confirmed by the population pharmacokinetic analysis (absence of relationship between vinflunine clearance and biology markers of hepatic impairment). However, dose adjustments are recommended in patients with liver impairment.
A pharmacokinetic phase I study was performed in 2 groups of patients with renal impairment classified according to the calculated creatinine clearance (CrCl) values: group 1 (n=13 patients) with moderate impairment (40 mL/min≤ CrCl ≤60 mL/min) and group 2 (n=20 patients) with severe impairment (20 mL/min≤ CrCl <40 mL/min). The pharmacokinetic results of this study indicated a reduction of vinflunine clearance when CrCl is decreased. This is further confirmed by the population pharmacokinetic analysis (56 patients with CrCl between 20 mL/min and 60 mL/min), showing that vinflunine clearance is influenced by the creatinine clearance value (Cockcroft and Gault formula). Dose adjustments are recommended in patients with moderate and severe renal impairment.
A pharmacokinetic phase I study of vinflunine was performed in elderly patients (n=46). Vinflunine doses were adjusted according to 3 age groups as shown below:
| Age (y) | Number of patients | Vinflunine (mg/m²) |
|---|---|---|
| [70–75[ | 17 | 320 |
| [75–80[ | 15 | 280 |
| ≥80 | 14 | 250 |
Vinflunine clearance was significantly decreased in patients ≥80 years old as compared to a control group of younger patients <70 years.
Pharmacokinetics of vinflunine was not modified for patients 70≤ age <75 years and 75≤ age <80 years.
Based on both PK and safety data, dose reductions are recommended in the elder groups: 75≤ age <80 years; and age ≥80 years. For further cycles the dose should be adjusted in the event of toxicities.
According to the population pharmacokinetic analysis, neither gender nor performance status (ECOG score) had an impact on vinflunine clearance which is directly proportional to body surface area.
Imaging distribution studies following radioactive vinflunine in rats, illustrated that the compound levels in lungs, kidneys, liver, salivary and endocrine glands, and gastrointestinal tract were rapidly higher than those in blood.
Preclinical data revealed moderate to severe neutropenia and mild anaemia, in all species tested, with liver toxicity in dogs and rats (characterized by dose-dependent increases in liver transaminases and hepatic necrosis/hepatocellular alterations at high doses). These toxic effects were dose-related and fully or-partially reversible following a 1-month recovery period. Vinflunine did not induce peripheral neuropathy in animals.
Vinflunine has shown to be clastogenic (induces chromosome breakage) in the in vivo micronucleus test in rat as well as mutagenic and clastogenic in a mouse lymphoma assay (without metabolic activation).
The carcinogenic potential of vinflunine has not been studied.
In the reproduction studies, vinflunine appeared to be embryolethal and teratogenic in rabbits and teratogenic in rats. During the pre- and post-natal development study in rat, vinflunine induced malformations of the uterus and vagina in 2 females, and adversely affected mating and/or ovule implantation and markedly lowered the number of concepti.
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