Vinorelbine Alvogen Mechanism of Action

Pharmacotherapeutic group: Vinca alkaloids and analogues. ATC Code: L01C A04.
Pharmacology: Pharmacodynamics: Mechanism of action: Vinorelbine Alvogen is an antineoplastic drug of the vinca alkaloid family but unlike all the other vinca alkaloids, the catharantine moiety of vinorelbine has been structurally modified. At the molecular level, it acts on the dynamic equilibrium of tubulin in the microtubular apparatus of the cell. It inhibits tubulin polymerization and binds preferentially to mitotic microtubules, affecting axonal microtubules at high concentrations only. The induction of tubulin spiralization is less than that produced by vincristine.
Vinorelbine Alvogen blocks mitosis at G2-M, causing cell death in interphase or at the following mitosis.
Safety and efficacy of vinorelbine in paediatric patients have not been established. Clinical data from two Phase II studies using intravenous vinorelbine in 33 and 46 paediatric patients with recurrent solid tumours, including rhabdomyosarcoma, other soft tissue sarcoma Ewing sarcoma, liposarcoma, synovial sarcoma, fibrosarcoma, central nervous system cancer, osteosarcoma, neuroblastoma, at doses of 30 to 33.75 mg/m² D1 and D8 every 3 weeks or once weekly for 6 weeks every 8 weeks, showed no meaningful clinical activity. The toxicity profile was similar to that reported in adult patients (see Dosage & Administration).
Pharmacokinetics: Pharmacokinetic parameters of vinorelbine were evaluated in blood.
Absorption: After oral administration, vinorelbine is rapidly absorbed and the T_max is reached between 1.5 to 3 h with a blood concentration peak (C_max) of approximately 130 ng/ml after a dose of 80 mg/m². Absolute bioavailability is approximately 40% and a simultaneous intake of food does not alter the exposure to vinorelbine.
Oral vinorelbine at 60 and 80 mg/m² leads to blood exposure comparable to that achieved with intravenous vinorelbine at 25 and 30mg/m², respectively.
The blood exposure to vinorelbine increases proportionally with the dose up to 100 mg/m². Interindividual variability of the exposure is similar after administration by intravenous and oral routes.
Distribution: The steady-state volume of distribution is large, on average 21.2 l/kg (range: 7.5-39.7 l/kg), which indicates extensive tissue distribution.
Binding to plasma proteins is weak (13.5%), vinorelbine binds strongly to blood cells and especially to platelets (78%).
There is a significant uptake of vinorelbine in lungs, as assessed by pulmonary surgical biopsies which showed concentration up to a 300-fold higher concentration than in serum. Vinorelbine is not found in the central nervous system.
Biotransformation: All metabolites of vinorelbine are formed by CYP3A4 isoform of cytochromes P450, except 4-O-deacetylvinorelbine likely to be formed by carboxylesterases. 4-O-deacetylvinorelbine is the only active metabolite and the main one observed in blood.
Neither sulphate nor glucuronide conjugates are found.
Elimination: The mean terminal half-life of vinorelbine is around 40 hours. Blood clearance is high, approaching hepatic blood flow, and is 0.72 l/h/kg (range: 0.32-1.26 l/h/kg).
Renal elimination is low (<5 % of the dose administered) and consists mostly in parent compound. Biliary excretion is the predominant elimination route of both unchanged vinorelbine, which is the main recovered compound, and its metabolites.
Special populations: Renal and liver impairment: The effects of renal dysfunction on the pharmacokinetics of vinorelbine have not been studied. However, dose reduction in case of reduced renal function is not indicated with vinorelbine due to the low level of renal elimination.
Pharmacokinetics of orally administered vinorelbine were not modified after administration of 60 mg/m² in 7 patients with mild hepatic impairment (bilirubin <1.5 x ULN, and ALAT and/or ASAT between 1.5 and 2.5 x ULN) and of 50 mg/m² in 6 patients with moderate hepatic disorder (bilirubin between 1.5 and 3 x ULN, whatever the levels of ALAT and ASAT). Total clearance of vinorelbine was neither modified between mild and moderate impairment nor was it altered in hepatically impaired patients when compared with clearance in patients with normal liver function.
No data is available for patients with severe liver impairment, therefore Vinorelbine Alvogen is contra-indicated in these patients (see Dosage & Administration, Contraindications, and Precautions).
Elderly: A study with oral vinorelbine in elderly patients (≥70 years) with NSCLC demonstrated that pharmacokinetics of vinorelbine were not influenced by age. However, since elderly patients are frail, caution should be exercised when increasing the dose of Vinorelbine Alvogen soft capsule (see Dosage & Administration).
Pharmacokinetics/Pharmacodynamic relationships: A strong relationship has been demonstrated between blood exposure and depletion of leucocytes or PMNs.
Toxicology: Preclinical safety data: Pre-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.
Vinorelbine induced chromosome damages but did not cause mutations in Ames test. It is assumed that vinorelbine can cause mutagenic effects (induction of aneuploidy of polyploidy) in man.
In animal reproductive studies, vinorelbine was embryo-feto-lethal and teratogenic.
No haemodynamic effects were found in dogs receiving vinorelbine at maximal tolerated dose; only some minor, non-significant disturbances of repolarisation were observed as with other vinca alkaloids tested.
No effect on the cardiovascular system was observed in primates receiving repeated doses of vinorelbine 2 mg/kg over 39 weeks.