Evaluation of oral versus intravenous dose of vinorelbine to achieve equivalent blood exposures in patients with solid tumours

Abstract

Patient's preference is for oral chemotherapy when both oral and i.v. are available, provided that efficacy is equivalent. Reliable switch from oral to i.v. is possible if correspondence between respective doses has been established. Vinorelbine oral was developed as a line extension of VRL i.v. on the basis that similar AUCs result in similar activities. From a first crossover study on 24 patients receiving VRL 25 mg/m2 i.v. and 80 mg/m2 oral data extrapolation concluded on AUCs bioequivalence between Vinorelbine 30 mg/m2 i.v. and 80 mg/m2 oral. A new trial was performed to support this calculation. In a crossover design study on patients (PS 0-1) with advanced solid tumours (44% breast carcinoma), VRL was administered (30 mg/m2 i.v., 80 mg/m2 oral) with a standard meal and 5-HT3 antagonists, at 2 weeks interval. Pharmacokinetics was performed over 168 h and VRL was measured by LC-MS/MS. Statistics included bioequivalence tests. Forty-eight patients were evaluable for PK: median age 58 years (25-71), PS0/PS1: 20/28, M/F: 11/37. Mean AUCs were 1,230 +/- 290 and 1,216 +/- 521 ng/ml for i.v. and oral, respectively. The confidence interval of the AUC ratio (0.83-1.03) was within the required regulatory range (0.8-1.25) and proved the bioequivalence between the two doses. The absolute bioavailability was 37.8 +/- 16.0%, and close to the value from the first study (40%). Patient tolerability was globally comparable between both forms with no significant difference on either haematological or non-haematological toxicities (grade 3-4). This new study, conducted on a larger population, confirmed the reliable dose correspondence previously established between vinorelbine 80 mg/m2 oral and 30 mg/m2 i.v.

Dose-Ranging Study of Metronomic Oral Vinorelbine in Patients with Advanced Refractory Cancer

“…The linearity of oral VRL pharmacokinetics already shown in the range 60 to 100 mg/m 2 is now confirmed in the lower range of doses (24,26). Low blood concentrations of VRL and DVRL fitted well with the simulated profiles achieved from a previous study and illustrated a continuous and stable exposure to both VRL and DVRL throughout the treatment (19). Achieved in this trial, steady-state concentrations were found in vitro to optimally inhibit proliferation of endothelial cell and induce expression anti-angiogenic molecular effects of endothelial cells (39).…”

“…The profiles of observed concentrations were in agreement with those simulated using a body surface area of 1.7 m 2 and the dose-adjusted data from a previous study performed at usual dose level (80 mg/m 2 ; ref. 19). …”

“…Oral vinorelbine (VRL) has shown bioavailability of 40%, which is practically not influenced by food or age, moderate interpatient variability, and linear pharmacokinetics (17)(18)(19)(20). Its metabolism has been elucidated and only 4-O-deacetylvinorelbine (DVRL) has been found active (21)(22)(23)(24).…”

The bioanalysis of vinorelbine and 4‐O‐deacetylvinorelbine in human and mouse plasma using high‐performance liquid chromatography coupled with heated electrospray ionization tandem mass–spectrometry

“…The drug can be dosed orally or intravenously and inhibits the polymerization of tubulin dimers into microtubules, resulting in the disruption of mitotic spindle formation in dividing cells (Bourgeois et al, 2007).…”

“…The absorption of oral vinorelbine is rapid (0.75-3 h) (Bourgeois et al, 2007;Gebbia and Puozzo, 2005;Jehl et al, 1991;Lush et al, 2005) with maximum concentrations (C max ) of approximately 100 ng/mL after administration of 80 mg/m 2 (Gebbia and Puozzo, 2005). After intravenous administration of 25 mg/m 2 much higher C max values of approximately 800 ng/mL were reported (Gebbia and Puozzo, 2005).…”