Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antineoplasic agents, Vinca alkaloids and analogues, ATC code: L01CA05

Mechanism of action
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.

Clinical efficacy and safety
One phase III and two phase II trials support the use of Javlor for treatment of advanced or metastatic transitional cell carcinoma of the urothelium as second-line therapy after failure of a prior platinum- containing regimen.

In the two multi-centre open-label, single-arm phase II clinical trials a total of 202 patients were treated with vinflunine.

In the multi-centre, open-label controlled phase III clinical trial, 253 patients were randomised to treatment with vinflunine + BSC (best supportive care) and 117 patients to the BSC arm.
The median overall survival was 6.9 months (vinflunine + BSC) vs. 4.6 months (BSC), but the difference did not reach statistical significance; hazard ratio 0.88 (95% CI 0.69, 1.12). However a statistically significant effect was seen on progression-free survival. Median PFS was 3.0 months (vinflunine + BSC) vs 1.5 months (BSC) (p=0.0012).

In addition a pre-specified multivariate analysis performed on the ITT population demonstrated that vinflunine had a statistically significant treatment effect (p=0.036) on overall survival when prognostic factors (PS, visceral involvement, alkaline phosphatases, haemoglobin, pelvic irradiation) were taken into consideration; hazard ratio 0.77 (95% CI 0.61, 0.98). A statistically significant difference on overall survival (p=0.040) was also seen in the eligible population (which excluded 13 patients with clinically significant protocol violations at baseline who were not eligible for treatment); hazard ratio 0.78 (95% CI 0.61, 0.99). This is considered the most relevant population for the efficacy analysis, as it most closely reflects the population intended for treatment.

Efficacy was demonstrated in both patients with or without prior cisplatin use.
In the eligible population, the subgroup analyses according to the prior cisplatin use versus BSC on overall survival (OS) showed a HR (95% CI) = [0.64 (0.40 – 1.03); p=0.0821] in the absence of prior cisplatin, and a HR (95% CI) = [0.80 (0.60 – 1.06); p=0.1263] in the presence of prior cisplatin. When adjusted on prognostic factors, the analyses of OS in the subgroups of patients without or with prior cisplatin showed a HR (95% CI) = [0.53 (0.32 – 0.88); p=0.0143] and a HR (95% CI) = [0.70 (0.53 – 0.94); p=0.0174], respectively.
In the subgroup analyses of prior cisplatin use versus BSC for progression free survival (PFS), the results were: HR (95% CI) = [0.55 (0.34 – 0.89); p=0.0129] in the absence of prior cisplatin, and a HR (95% CI) = [0.64 (0.48 – 0.85); p=0.0040] in the presence of prior cisplatin. When adjusted on prognostic factors, the analyses of PFS in the subgroups of patients without or with prior cisplatin showed a HR (95% CI) = [0.51(0.31 – 0.86); p=0.0111] and a HR (95% CI) = [0.63(0.48 – 0.84); p=0.0016], respectively.

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Javlor in all subsets of the paediatric population in the treatment of ureter and bladder carcinoma and the treatment of breast carcinoma (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

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.

Distribution
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.
Biotransformation
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.

Elimination
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 (2/3) and urine (1/3).
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).

Pharmacokinetics in special populations

Hepatic impairment
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 (see section 4.2).

Renal 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 (see section 4.2).

Elderly (≥ 75 years)
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:

Number of
Age (y)                          Vinflunine (mg/m²) patients
[ 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 (see section 4.2).

Others

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.