Navelbine Capsule Mechanism of Action

Pharmacotherapeutic group: Cytostatic - Antineoplastic drug.
Pharmacology: Mechanism of action: Navelbine is a cytostatic antineoplastic of the vinca alkaloid group. The molecular target of its activity is tubulin/microtubules dynamic equilibrium. Navelbine inhibits the polymerization of tubulin. lt acts preferentially on mitotic microtubules and affects axonal microtubules only at high concentration.
The effects on tubulin spiralization are Iower than with vincristine. Navelbine blocks mitosis in phase G2+M and induces cell death at interphase or at the following mitosis.
Pharmacokinetics: Absorption: After oral administration, vinorelbine is rapidly absorbed and the Tmax is reached between 1.5 to 3 h with a blood concentration peak (C_max) 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.
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 l.kg^-1 (range: 7.5 - 39.7 l.kg^-1), 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 CYP 3A4 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 group: 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 hepatic disorder (bilirubin <1.5 x ULN, and ALT and/or AST 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 ALT and AST).
Total clearance of vinorelbine was neither modified between mild and moderate liver impairment nor was it altered in hepatically impaired patients when compared with the clearance in patients with normal liver function. No data are available for patients with severe hepatic disorder, therefore the use of Navelbine is not recommended.
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 Navelbine soft capsule.
Pharmacokinetics/Pharmacodynamic relationships: A strong relationship has been demonstrated between blood exposure and depletion of leucocytes or PMNs.
Toxicology: Preclinical safety data: Vinorelbine induced chromosome damages but was not mutagenic in Ames test. It is assumed that vinorelbine can cause mutagenic effects (induction aneuploidy and 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 found as with other vinca alkaloids tested. No effect on the cardiovascular system was observed in primates receiving repeated doses of vinorelbine over 39 weeks.