Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Accord Healthcare Limited, Sage House, 319 Pinner Road, North Harrow, Middlesex, HA1 4HF, United Kingdom
Pharmacotherapeutic group: Antineoplastic agents. Plant alkaloids and other natural products. Vinca alkaloids and analogues
ATC code: L01CA04
Vinorelbine is an antineoplastic active substance of the vinca alkaloid family, but in contrast to all other vinca alkaloids the catharanthine portion of vinorelbine has undergone a structural modification. On the molecular level, it affects the dynamic equilibrium of tubulin in the microtubular system of the cell.
Vinorelbine inhibits tubulin polymerisation and binds preferentially to mitotic microtubules, only affecting axonal microtubules at high concentrations. The spiralisation of the tubulin is induced to a lesser degree than with vincristine. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.
The safety and efficacy of vinorelbine in the paediatric population have not yet been completely established. Clinical data from phase II trials using intravenous vinorelbine in 33 and 46 paediatric patients with recurring solid tumours, including rhabdomyosarcoma, other soft tissue sarcomas, Ewing’s sarcoma, liposarcoma, synovial sarcoma, fibrosarcoma, cancer of the central nervous system, osteosarcoma and neuroblastoma, at doses of 30 to 33.75 mg/m² D1 and D8 every 3 weeks, or once a week for 6 weeks every 8 weeks, did not show significant clinical activity. The toxicity profile was similar to that reported in adult patients (see section 4.2).
The pharmacokinetic parameters of vinorelbine were tested in blood.
The volume of distribution at the steady state is large, with a mean value of 21.2 l.kg-1 (range: 7.5-39.7 l.kg-1), indicating widespread distribution in the tissues.
There is low binding to plasma protein (13.5%), but strong binding to blood cells, 78% of the total blood-bound vinorelbine was associated with platelets and 4.8% of the total blood-bound vinorelbine was associated with lymphocytes.
Evaluation using surgical biopsies of the lungs showed significant retention of vinorelbine in the lungs, with a concentration 300 times greater than in plasma. No vinorelbine was detected in the central nervous system.
All the vinorelbine metabolites result from the CYP3A4 isoform of cytochrome P450, except 4-O-diacetylvinorelbine, which is probably obtained by the action of carboxylesterases. 4-O-diacetylvinorelbine is the only active metabolite and the principal one observed in blood.
No sulfate conjugates or glucuronide were found.
The mean terminal half life of vinorelbine is approximately 40 hours. Blood clearance is high, approaching the hepatic blood flow. Its mean value is 0.72 l.h-1.kg-1 (range: 0.32-1.26 l.h-1.kg-1).
Renal clearance is low (<20% of the intravenous dose administered) and consists primarily of parent compounds.
The main route of elimination is via the bile ducts, both for metabolites and for unaltered vinorelbine, which is the principal compound that is recovered.
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 (see sections 4.2 and 4.4).
A study on Vinorelbine solution in elderly patients (≥70 years) with non-small cell lung cancer (NSCLC) showed that the pharmacokinetics of vinorelbine is not influenced by age. However, bearing in mind that elderly patients are frail, precaution is necessary when increasing the dose of Vinorelbine solution (see section 4.2).
A strong relationship has been demonstrated between blood exposure and PMN or leukocyte reductions.
The limiting toxicity in animals is bone marrow depression. In animal studies, vinorelbine induced aneuploidy and polyploidy.
It can be assumed that vinorelbine can also cause genotoxic effects in humans (induction of aneuploidy and polyploidy).
The results of studies for carcinogenic potential in mice and rats were negative but only low doses have been tested.
In animal reproductive studies, effects were observed at subtherapeutic dosages. Embryo- and fetotoxicity were seen, such as intra-uterine growth retardation and delayed ossification. Teratogenicity (fusion of the vertebrae, missing ribs) was observed at maternally toxic doses. In addition, spermatogenesis and secretion of prostate and seminal vesicles were reduced, but fertility in rats was not diminished."
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