Chemical formula: C₄₅H₅₄N₄O₈ Molecular mass: 778.947 g/mol PubChem compound: 44424639
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.
Pharmacokinetic parameters of vinorelbine were evaluated in blood.
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.
The blood exposure to vinorelbine increases proportionally with the dose up to 100mg/m². Interindividual variability of the exposure is similar after administration by intravenous and oral routes.
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.
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.
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-1.kg-1 (range: 0.32-1.26 l.h-1.kg-1).
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.
The effects of renal failure on the availability of vinorelbine have not been evaluated.
However, due to the low degree of renal clearance, a dose reduction is not necessary in case of renal failure.
A first study reported the effects of hepatic failure on the pharmacokinetics of vinorelbine. This study was conducted on patients with liver metastases from breast cancer, and concluded that changes in the mean clearance of vinorelbine were only detected when over 75% of the liver was involved.
A phase I, dose-adjustment pharmacokinetic study was conducted on cancer patients with hepatic failure: 6 patients with moderate failure (bilirubin <2 x ULN and transaminases <5 x ULN) treated with doses of up to 25 mg/m² and 8 patients with severe failure (bilirubin >2 x ULN and/or transaminases >5 x ULN) treated with doses of up to 20 mg/m². The total mean clearance in these two patient subgroups was similar to that of patients with normal liver function. Therefore, the pharmacokinetics of vinorelbine is not modified in patients who suffer moderate or severe hepatic failure.
Nonetheless, as a precaution, the administration of a reduced dose of 20 mg/m² and close monitoring of blood parameters is recommended in patients with severe hepatic failure.
A study with 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.
A strong relationship has been demonstrated between blood exposure and depletion of leucocytes or PMNs.
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 observed as with other vinca alkaloids tested. No effect on the cardiovascular system was observed in primates receiving repeated doses of vinorelbine over 39 weeks.
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