Vinflunine

Abstract

Vinflunine is a novel bifluorinated vinca alkaloid that appears to differ from other class members in terms of its tubulin-binding properties and inhibitory effects on microtubule dynamics. Notably, it demonstrated superior in vivo antitumour activity to that of vinorelbine in a range of transplantable murine and human tumours. In a randomized, open-label, multicentre phase III trial in adult patients with advanced transitional cell carcinoma of the urothelium who experienced progression after first-line platinum-containing chemotherapy (n = 370), median overall survival (OS; primary endpoint) was 6.9 months for intravenous vinflunine plus best supportive care (BSC) recipients versus 4.6 months for BSC alone recipients in the intent to treat (ITT) population. The difference in OS between treatment groups was not significant in the ITT population; however, there was a significant improvement in OS for vinflunine plus BSC recipients in the ITT population after adjusting for prespecified prognostic factors, and in the analysis of the eligible population (ITT population excluding baseline protocol violations). In the latter, median OS was 6.9 months with vinflunine plus BSC versus 4.3 months with BSC alone after a median follow-up of approximately 1.8 years and again after a median follow-up of approximately 3.6 years. Progression-free survival, objective response rate and disease control rate were significantly improved with vinflunine plus BSC versus BSC alone. The most frequent treatment-related adverse events in vinflunine recipients included myelosuppression (e.g. neutropenia) and gastrointestinal symptoms (e.g. constipation). In general, adverse events with vinflunine were noncumulative and medically manageable.

How to manage intravenous vinflunine in cancer patients with renal impairment: results of a pharmacokinetic and tolerability phase I study

“…VFL is characterized by a high total blood clearance (>40 l h −1 ) and a large volume of distribution (2422 l) suggesting that the drug is extensively distributed into tissues. VFL is moderately bound to plasma proteins (40-78%), with a negligible binding to α1-glycoprotein and platelets [9]. As for the other vinca alkaloids, VFL exhibits an important metabolism.…”

“…For vinflunine, a phase I mass balance study indicates that this drug is predominantly excreted via the biliary route however the renal excretion is not negligible and superior to that observed with vinorelbine: two-thirds of the recovered VFL dose is excreted into the faeces while one-third is excreted into the urine [9]. Consequently, it could be questioned whether a compromised renal function would affect the PK of VFL, possibly resulting in drug overexposure and increased toxicity.…”

Phase I dose-escalation study of vinflunine hard capsules administered twice a day for 2 consecutive days every week in patients with advanced/metastatic solid tumors

“…studies using the once every 3 weeks dosing schedule, no accumulation was observed for either VFL or DVFL [9]. In the current study with a fractionated oral regimen, the accumulation was predictable: the slight accumulation observed for VFL over the 4 consecutive administrations of the first week (inter-dosing interval of 12 h) and the absence of accumulation between successive weeks (inter-dosing interval of 132 h) are consistent with the known terminal half-life of VFL (about 40 h) [9]. The higher accumulation ratios calculated for DVFL are also consistent with the longer terminal half-life reported for DVFL (about 4-6 days) [9].…”

“…form of vinflunine, three (3) dosing schedules were investigated: once every 3 weeks [6], twice every 3 weeks on Day 1 and Day 8 [7], and a weekly schedule [8]. The once every 3 weeks schedule has proved its efficacy and is currently registered for use in transitional carcinoma of urothelial cell (TCCU) patients [9]. This dosing schedule is also the most convenient for the patients over the other i.v.…”

Influence of age on the pharmacokinetics of i.v. vinflunine: Results of a phase I trial in elderly cancer patients

“…10 Pharmacokinetic properties of VFL were fully characterized during clinical development. 11 Following intravenous (IV) administration to patients, VFL is eliminated according to a multi-exponential decay with a rapid decrease of blood concentrations after the end of infusion. The terminal half-life (T ½ z ) is close to 40 h. The volume of distribution of the terminal phase is large (2 422 L), suggesting an important tissue distribution and uptake.…”