Navelbine Mechanism of Action

Antineoplastic.
Pharmacology: Pharmacodynamics: Vinorelbine is a cytostatic antineoplastic agent belonging to the vinca alkaloid family although unlike the other vinca alkaloids the catharantine part of vinorelbine has been structurally modified. On a molecular level, it acts on the dynamic equilibrium of tubulin within the cell microtubular apparatus. Vinorelbine inhibits tubulin polymerisation. It acts preferentially on the mitotic microtubules and only affects axonal microtubules at high concentrations. Its tubulin spiralising potential is less than that of vincristine.
Vinorelbine blocks mitosis in G2-M phase and causes cell death in interphase or at the subsequent mitosis.
The safety and efficacy of vinorelbine have not been established in the paediatric population. Clinical data from two uncontrolled Phase II studies (single arm) using vinorelbine as a solution for injection in 33 and 46 paediatric patients suffering from recurrent solid tumours including rhabdomyosarcomas, soft tissue sarcomas, Ewing's sarcomas, liposarcomas, synovial sarcomas, fibrosarcomas, central nervous system cancers, osteosarcomas and neuroblastomas at doses of 30 or 33.75 mg/m² on days 1 and 8 every 3 weeks or once per week for 6 weeks every 8 weeks did not show significant clinical efficacy. The toxicity profile is similar to that reported for adult patients.
Pharmacokinetics: The pharmacokinetic parameters of vinorelbine have been evaluated in blood.
Absorption: Following oral administration, vinorelbine is rapidly absorbed with a T_max achieved at 1.5 to 3 h and a peak plasma concentration (C_max) of approximately 130 ng/mL after administration at the dose of 80 mg/m². Its absolute bioavailability is approximately 40% and vinorelbine exposure is not changed by simultaneous ingestion of food. Oral vinorelbine administered at doses of 60 and 80 mg/m² results in similar blood exposure to the exposure with doses of 25 and 30 mg/m² of the intravenous form respectively.
Inter-individual variability of exposure is equivalent after IV and oral administration.
Blood exposure increased proportionately to dose at doses up to 100 mg/m².
Distribution: Plasma protein binding is low (13.5%), although vinorelbine is highly bound to blood cells, particularly to platelets (78%).
The steady state volume of distribution is large, on average 21.2 l.kg-1 (range 7.5-39.7 l.kg-1) indicating an extensive tissue distribution.
Extensive amounts of vinorelbine enter lung tissues as shown by the mean tissue/serum concentration ratio found from surgical lung biopsy, which is over 300.
Vinorelbine has not been found in the central nervous system.
Biotransformation: All of the metabolites of vinorelbine are formed by the cytochrome P450 CYP3A4 isoform, except for the 4-O-deacetylvinorelbine which appears to be formed by carboxylesterases.
4-0-deacetyl-vinorelbine is the only active metabolite and the main metabolite found in blood.
No sulphate or glucuronide conjugates have been detected.
Elimination: The elimination half-life of vinorelbine is approximately 40 hours.
Blood clearance is high similar to hepatic blood flow, and is 0.72 l.h-1/kg-1 (range: 0.32 to 1.26 l.h-1.kg-1).
Renal elimination is low (<5% of the dose administered) and it is mostly the unchanged substance which is found. Biliary excretion is the main elimination route, both as metabolites and as unchanged vinorelbine (main compound found).
Special populations: Renal impairment: The effects of renal dysfunction on vinorelbine elimination have not been studied. In view of the low renal elimination of vinorelbine a reduction in dose is not indicated in patients with low level of renal elimination.
Liver impairment: The pharmacokinetics of oral vinorelbine were not changed after administration of a dose of 60 mg/m²/week in mild hepatic disorder (bilirubin <1.5 x ULN, and AST and/or ALT 1.5 to 2.5 x ULN), and the dose of 50 mg/m²/week in moderate hepatic disorder (bilirubin 1.5 to 3 x ULN, regardless of ALT or AST level).
Vinorelbine soft-gelatin capsule has not been studied in patients suffering from severe hepatic disorder and its use is therefore not recommended in these patients.
Elderly patients: A study of oral vinorelbine administration to elderly patients (>70 years old) suffering from NSCLC showed that age does not influence the pharmacokinetics of vinorelbine.
As elderly people are frail, however, caution is required when doses of vinorelbine are increased.
Relationships between pharmacokinetics and pharmacodynamics: A close correlation has been found between blood exposure and leukocyte and depletion of leukocytes or neutrophils.
Toxicology: Preclinical Safety Data: Mutagenic and carcinogenic potential: Binding of vinorelbine to the achromatic spindle during mitosis may cause incorrect chromosome distribution. In animal studies, intravenous vinorelbine cause aneuploidy and polyploidy. It is possible that vinorelbine may also cause mutagenic effects (induction of aneuploidy) in human beings.
Carcinogenicity studies in which vinorelbine was administered intravenously once every two weeks in order to avoid the toxic effects of the substance were negative.
Reproduction studies: Vinorelbine has been shown to be embryo and foeto-lethal and teratogenic in animal reproduction studies. The no adverse effect level in the rat was 0.26 mg/kg every 3 days.
After peri- or postnatal administration of a dose of 1.0 mg/kg IV every 3 days to the rat, delayed weight gain was seen in the offspring until the 7th week of life.
Pharmacological safety: No haemodynamic effects have been found in dogs which receive vinorelbine at the maximum tolerated dose: only minor non-significant repolarisation disturbances were seen, as applies to the other vinca alkaloids tested. No cardiovascular system effects were seen in primates which received repeated doses of vinorelbine for 39 weeks.
Overdose in animals: The symptoms of overdose in animals tested consisted of hair loss, abnormal behaviour (prostration, drowsiness), pulmonary lesions, weight loss and various degrees of bone marrow aplasia.