Navelbine Mechanism of Action

vinorelbine tartrate


OEP Phils


Full Prescribing Info
Pharmacology: Vinorelbine 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 blocks mitosis at G2-M, causing cell death in interphase or at the following mitosis.
Safety and efficacy of vinorelbine in pediatric patients have not been established. Clinical data from two single arm Phase II studies using intravenous vinorelbine in 33 and 46 paediatric patients with recurrent solid tumors, 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.
Pharmacokinetics: Pharmacokinetic parameters of vinorelbine were evaluated in blood.
Absorption: After oral administration, vinorelbine is rapidly absorbed and the Tmax is reached between 1.5 to 3 h with a blood concentration peak (Cmax) 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 30 mg/m2, respectively of the IV form.
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 IV and oral routes.
Distribution: The steady-state volume of distribution is large, on average 21.2 (range: 7.5 - 39.7, 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 sulfate 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 patients groups: 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 patients with mild liver impairment (bilirubin <1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN) and of 50 mg/m2 in patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT). No data is available for patients with severe liver impairment, therefore vinorelbine is contraindicated in these patients.
Elderly patients: 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 Soft-Gelatin Capsule.
Pharmacokinetics/Pharmacodynamic relationships: A strong relationship has been demonstrated between blood exposure and depletion of leucocytes or PMNs.
Toxicology: Preclinical Safety Data: Mutagenic and carcinogenic potential: The interaction of vinorelbine with the achromatic spindle during mitosis may lead to an incorrect distribution of chromosomes. In animal studies, intravenous vinorelbine caused aneuploidy and polyploidy. It is possible that vinorelbine may also have mutagenic effects (induction of aneuploidy) in humans.
The carcinogenicity studies in which vinorelbine was administered intravenously once every two weeks in order to avoid the toxic effects of the product proved negative.
Reproduction studies: In animal reproduction studies, vinorelbine has been shown to have embryolethal, fetolethal and teratogenic effects. The nontoxic dose in the rat was 0.26 mg/kg every 3 days.
After perinatal or postnatal administration to rats at a dose of 1.0 mg/kg IV every 3 days, retarded weight gain was observed in the offsprings until the 7th week of life.
Pharmacological safety: No hemodynamic effect has been observed in dogs treated at the maximum tolerated dose; only non-significant minor repolarisation disorders appeared, as with the other vinca alkaloids tested. No effect on the cardiovascular system was observed in primates treated with repeated doses of vinorelbine for 39 weeks.
Animal overdosage: The symptoms of overdosage in the animals tested consisted of hair loss, abnormal behaviour (prostration, somnolence), pulmonary lesions, weight loss and varying degrees of bone marrow aplasia.
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