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HomeProduct name listVinorelbine

Vinorelbine

Vinorelbine Structural

What is Vinorelbine?

Absorption

Vinorelbine is rapidly absorbed with peak serum concentration reached within 2 hours .
Vinorelbine is highly bound to platelets and lymphocytes and is also bound to alpha 1-acid glycoprotein, albumin, and lipoproteins .

Toxicity

Due to the wide array of adverse effects of this drug, the toxicity of is categorized into organ systems .
Hematologic: Granulocytopenia was the primary dose-limiting toxicity with vinorelbine tartrate therapy; it is generally reversible and not cumulative. In one study, granulocytopenia resulted in hospitalizations for fever and/or sepsis in 8% of NSCLC and 9% of breast cancer patients . Infectious (septic) deaths occurred in about 1% of patients. Grade 3 or 4 anemia occurred in about 1% of lung cancer and approximately 14% of breast cancer patients. Blood transfusions were administered to 18% of patients who received vinorelbine tartrate therapy. The incidence of Grade 3 and 4 thrombocytopenia was found to be less than 1% .
Neurologic: Mild to moderate peripheral neuropathy may occur. Symptoms of paresthesia and hypesthesia are reported as the most commonly reported neurologic toxicities of this drug. The loss of deep tendon reflexes (DTR) occurs in less than 5% of patients, according to one study. The development of severe peripheral neuropathy is rare .
Dermatologic: Alopecia has been reported in only about 12% of patients and is usually reported as mild. Vinorelbine tartrate is a moderate vesicant, leading to injection site reactions. Symptoms include erythema, pain at the injection site and vein discoloration occurred in about 1/3 of all patients. Chemical phlebitis along the vein, near the site of injection, has been reported .
Respiratory: Shortness of breath was reported in 3% of NSCLC and 9% of breast cancer patients, and was severe in 2% of each patient population. Interstitial pulmonary changes have been documented in a few patients .
Gastrointestinal: Mild or moderate nausea symptoms occurred in 32% of NSCLC and 47% of breast cancer patients treated with vinorelbine tartrate. Severe nausea was occurred infrequently (1% and 3% in NSCLC and breast cancer patients, respectively). Prophylactic administration of anti-emetics was not routine in patients treated with single-agent vinorelbine tartrate. Constipation occurred in about 28% of NSCLC and 38% of breast cancer patients. The paralytic ileus incidence of less than 2% of patients. Vomiting, diarrhea, anorexia and stomatitis were found to be mild or moderate and occurred in less than 20% of study patients .
Hepatic: Transient elevations of liver enzymes were reported without clinical symptoms. Cardiovascular: Chest pain was reported in 5% of NSCLC and 8% of breast cancer patients. Most reports of chest pain were in patients who had either a history of cardiovascular disease or tumor within the chest. There have been rare reports of myocardial infarction; however, these have not been shown definitely attributable to vinorelbine tartrate .
Other: Muscle weakness (asthenia) occurred in about 25% of patients with NSCLC and 41% of patients with breast cancer. It was usually mild or moderate but showed a linear increase with cumulative doses .
Several other toxicities reported in approximately 5% of patients include jaw pain, myalgia, arthralgia, headache, dysphagia, and skin rash. Hemorrhagic cystitis (bladder inflammation with blood in urine) and the syndrome of inappropriate ADH secretion were both reported in less than 1% of patients. The treatment of these entities are mainly symptomatic .
The carcinogenic potential of Vinorelbine has not been adequately studied. Vinorelbine has been demonstrated to affect chromosome number and likely the chromosome structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice were observed) .

Description

Vinorelbine is a semisynthetic vinca alkaloid differing from vinblastine in the catharantine moiety of the molecule. It is claimed to have a broad spectrum of action both in vifro and in vivo; clinically it has been found effective in the treatment of non-small cell lung cancer, advanced breast cancer, ovarian cancer and Hodgkins disease.

Originator

CNRS (France)

The Uses of Vinorelbine

Vinorelbine base is an antineoplastic agent with anti-mitotic properties.

The Uses of Vinorelbine

antimigraine, 5HT[1B/1D] agonist

Indications

Vinorelbine tartrate is indicated for adults in the treatment of advanced non-small cell lung cancer (NSCLC), as a single therapy or in combination with other chemotherapeutic drugs .
Used in relapsed or refractory Hodgkin lymphoma, in combination with other chemotherapy agents .
For the treatment of desmoid tumor or aggressive fibromatosis, in combination with methotrexate .
For the treatment of recurrent or metastatic squamous cell head and neck cancer .
For the treatment of recurrent ovarian cancer .
For the treatment of metastatic breast cancer, in patients previously treated with anthracyline and/or taxane therapy .
For the treatment of HER2-positive, trastuzumab-resistant, advanced breast cancer in patients previously treated with a taxane, in combination with trastuzumab and everolimus .

Background

Vinorelbine is an anti-mitotic chemotherapy drug that is used in the treatment of several types of malignancies, including breast cancer and non-small cell lung cancer (NSCLC) . It was initially approved in the USA in 1990's for the treatment of NSCLC .
It is a third-generation vinca alkaloid. The introduction of third-generation drugs (vinorelbine, gemcitabine, taxanes) in platinum combination improved survival of patients with advanced NSCLC, with very similar results from the various drugs. Treatment toxicities are considerable in the combination treatment setting .
A study was done on the clearance rate of vinorelbine on individuals with various single polymorphonuclear mutations. It was found that there was 4.3-fold variation in vinorelbine clearance across the cohort, suggesting a strong influence of genetics on the clearance of this drug .

What are the applications of Application

Vinorelbine base is an antineoplastic agent with anti-mitotic properties

Definition

ChEBI: A vinca alkaloid with a norvinblastine skeleton.

Manufacturing Process

(+/-)-5-Ethyl-1,2,3,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester and (+)-tartaric acid were dissolved in hot 95% ethanol. The resulting solution was allowed to slowly cool to room temperature and refrigerated overnight. The crystals were filtered, washed with cold ethanol, and recrystallized from 95% ethanol, cooling as before to give the (+)-tartrate salt of (+)-5-ethyl- 1,2,3,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester.
The salt of (+)-5-ethyl-1,2,3,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester was dissolved in on ice, and 3 N sodium hydroxide was slowly added until the pH reached 11-12. The solution was extracted with chloroform, dried (Na 2 SO 4 ) and evaporated in vacuum to give (+)-5-ethyl-1,2,3,6-tetrahydro- pyridine-3-carboxylic acid ethyl ester as a mobile oil.
Reduction of (+)-5-ethyl-1,2,3,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester with LiAlH 4 in THF, using the usual protocols associated with this reagent gave the (+)-5-ethyl-1,2,3,6-tetrahydro-pyridine-3-ol. This material was used directly in the next step.
To a solution of the (+)-5-ethyl-1,2,3,6-tetrahydro-pyridine-3-ol in ethanol and triethylamine water, cooled equiv.) was added allyl bromide and the mixture heated at reflux for 12 h. The mixture was evaporated in vacuo and the residue dissolved in chloroform and washed with 5% aqueous K 2 CO 3 . The chloroform layer was dried (MgSO 4 ) and evaporated in vacuo to give the (+)- 1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-ol.
The (+)-1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-ol was converted into its methanesulfonate ester in the standard manner by treatment with methanesulfonic acid.
To a solution of the (+)-1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-methanesulfonate in acetone was added lithium bromide (6.9 g, 0.08 mol) and the suspension heated at reflux. The acetone was evaporated in vacuo, and the residue partitioned between chloroform and cold aqueous 5% K 2 CO 3 solution. The chloroform layer was dried (MgSO 4 ), filtered, and evaporated in vacuo to give a brown oil. Fractional distillation gave the (+)-1-allyl-5-ethyl- 1,2,3,6-tetrahydro-pyridin-3-bromide.
To a solution of N-phenylsulfonyl indole (5.14 g, 20 mmol) in dry THF (100 ml) under argon, and cooled to -65°C., was added t-butyl lithium (13 ml, 22 mmol, 1.7 M in pentane). The solution was allowed to warm to 0°C and stirred for 1 h. The above solution was added via canula to a stirred solution of dimethyloxalate (9.5 g, 80 mmol) in THF (250 ml) at 0°C. After 4 h at 0°C the mixture was quenched with saturated aqueous NH 4 Cl and extracted with ethyl acetate (3 times 100 ml). The dried (MgSO 4 ) extract was evaporated in vacuum, and the residue purified by chromatography over silica gel eluting with hexane/ethyl acetate (b 10:1) to give the N-phenylsulfonyl-2-methoxalyl indole (2.3 g, 34%). Melting point 111°-112°C (from ethyl acetate).
To the (+)-1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-bromide in a flame dried flask under argon was added Mg powder and dry THF. The mixture was heated at reflux and two drops of 1,2-dibromoethane added to initiate Grignard reagent formation. After 3 h the turbid suspension was cooled to room temperature and added to a solution of the N-phenylsulfonyl-2- methoxalyl indole in THF, at 0°C under argon. After 30 min the solution was quenched with saturated aqueous NH 4 Cl solution, and diluted with ethyl acetate. The dried (MgSO 4 ) extract was evaporated in vacuo to give the (+)- methyl 2-[2-(N-phenylsulfonyl)indolyl]-2-hydroxy-3-[3-(N-allyl 5-ethyl- 1,2,3,6-tetrahydro-peridine)]propionate consisting of a mixture of diastereomers at C-2 (1:1). For the purpose of characterization, one of the diastereomers was purified by chromatography over silica gel eluting with hexane/ethyl acetate/10% aqueous NH 4 OH/MeOH (15:3:1) to give the (+)- methyl 2-[2-(N-phenylsulfonyl)indolyl]-2-hydroxy-3-[3-(N-allyl-5-ethyl- 1,2,3,6-tetrahydro-pyridine)]propionate.
To a solution of the (+)-methyl 2-[2-(N-phenylsulfonyl)indolyl]-2-hydroxy-3- [3-(N-allyl-5-ethyl-1,2,3,6-tetrahydropyridine)]propionate (a mixture of diastereomers at C-2) in dry dimethoxyethane at -50°C under argon was added sodium naphthalenide (1 M in THF). The mixture was quenched with trifluoroacetic acid, and extracted with ethyl acetate (3 times 10 ml). The extract was washed with saturated aqueous NaHCO 3 solution, dried (MgSO 4 ) and evaporated in vacuo to give the (+)-methyl 2-(2-indolyl)-2-hydroxy-3-[3- (N-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridine )]propionate. The mixture of diastereomers was not separated but chromotagraphed over silica gel eluting with hexane/ethyl acetate/10% aqueous NH 4 OH/MeOH (5:1:1) to remove more polar impurities.
A solution of the (+)-methyl 2-(2-indolyl)-2-hydroxy-3-[3-(N-allyl-5-ethyl- 1,2,3,6-tetrahydro-pyridine)]propionate (mixture of diastereomers), and vindoline in 1% HCl/MeOH was heated at reflux for 2 h. The solution was evaporated in vacuo and the residue dissolved in chloroform and washed with saturated aqueous NaHCO 3 solution. The chloroform layer was dried over MgSO 4 , filtered, and evaporated to give a foam consisting of a mixture of S-and R-diastereomers. The diastereomeric mixture was separated by preparative HPLC eluting with hexane/CH 2 Cl 2 /MeOH/10% aqueous NH 4 OH to give S-(+)-4-acethoxy-9-[2-(1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-yl)-1- (1H-indol-2-yl)-1-methoxycarbonyl-ethyl]-3a-ethyl-5-hydroxy-8-methoxy-6- methyl-3a,4,5,5a,6,11,12,12b-octahydro-1H-6,12a-diaza-indeno[7,1- ca]fluorene-5-carboxylic acid methyl ester.
The S-(+)-4-acethoxy-9-[2-(1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3yl)-1- (1H-indol-2-yl)-1-methoxycarbonyl-ethyl]-3a-ethyl-5-hydroxy-8-methoxy-6- methyl-3a,4,5,5a,6,11,12,12b-octahydro-1H-6,12a-diaza-indeno[7,1- ca]fluorene-5-carboxylic acid methyl ester in 1,2-dichloroethane, containing proton sponge at 25°C, was treated with 1-chloroethyl chloroformate (0.056 ml, 0.512 mmol, 2.0 equiv.) and the resulting solution stirred for 3 h. The mixture was evaporated in vacuo, and the residue dissolved in methanol and heated at reflux for 3 h. The methanol was evaporated and the residue dissolved in chloroform and purified by chromatography over silica gel eluting with CHCl 3 , MeOH, 10% aqueous NH 4 OH (20:1) to give S-(+)-4-acethoxy-9- [2-(5-ethyl-1,2,3,6-tetrahydro-pyridin-3yl)-1-(1H-indol-2-yl)-1- methoxycarbonyl-ethyl]-3a-ethyl-5-hydroxy-8-methoxy-6-methyl- 3a,4,5,5a,6,11,12,12b-octahydro-1H-6,12a-diaza-indeno[7,1-ca]fluorene-5- carboxylic acid methyl ester.
To a solution of the S-(+)-4-acethoxy-9-[2-(5-ethyl-1,2,3,6-tetrahydro- pyridin-3yl)-1-(1H-indol-2-yl)-1-methoxycarbonyl-ethyl]-3a-ethyl-5-hydroxy- 8-methoxy-6-methyl-3a,4,5,5a,6,11,12,12b-octahydro-1H-6,12a-diaza- indeno[7,1-ca]fluorene-5-carboxylic acid methyl ester in dioxane and glacial acetic acid was added 37% aqueous formaldehyde and the mixture stirred at 35°C for 24 h. The solution was evaporated in vacuo and the residue suspended in chloroform and washed with cold aqueous 5% K 2 CO 3 solution. The chloroform layer was dried (MgSO 4 ), filtered, and evaporated. The residue was chromatographed eluting with EtOAc/MeOH, 10% NH 4 OH to give the product navelbine.

brand name

Navelbine (Pierre).

Therapeutic Function

Antineoplastic

Pharmacokinetics

Vinorelbine is a semi-synthetic vinca-alkaloid with a wide spectrum of anti-tumor activity. The vinca-alkaloids are considered spindle poisons. They work by interfering with the polymerization of tubulin, a protein responsible for building the microtubule system which appears during cell division in proliferating cancer cells .

Pharmacokinetics

This semisynthetic alkaloid is unique in having oral bioavailability, but it currently is available only for IV injection. The initial phase elimination half-life is on par with that observed for vincristine and vinblastine, and the terminal phase half-life is between 28 and 44 hours.

Clinical Use

Vinorelbine is particularly useful in the treatment of advanced non–small cell lung cancer and can be administered alone or in combination with cisplatin. It is thought to interfere with mitosis in dividing cells through a relatively specific action on mitotic microtubules.

Side Effects

Although dose-limiting granulocytopenia is the major adverse effect, potentially fatal interstitial pulmonary changes have been noted, and patients with symptoms of respiratory distress should be promptly evaluated. As with all vinca alkaloids, elimination is primarily hepatobiliary, and dosage reduction should be considered in patients with liver dysfunction.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: increased risk of neutropenia with clarithromycin; possible increased risk of ventricular arrhythmias with delamanid.
Antifungals: metabolism possibly inhibited by itraconazole, increased risk of neurotoxicity.
Antimalarials: avoid with piperaquine with artenimol.
Antipsychotics: avoid concomitant use with clozapine (increased risk of agranulocytosis).

Metabolism

Vinorelbine undergoes substantial hepatic elimination in humans. Two metabolites of vinorelbine have been identified in human blood, plasma, and urine; vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine has been demonstrated to be the primary metabolite of vinorelbine in humans, and has been shown to possess antitumor activity similar to vinorelbine , .
Vinorelbine is metabolized into two other minor metabolites, 20'-hydroxyvinorelbine and vinorelbine 6'-oxide .
Therapeutic doses of vinorelbine (30 mg/m2) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinorelbine is mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily , .
As the liver provides the main route for metabolism of the drug, patients with hepatic impairment may demonstrate increased toxicity with standard dosing, however, there are no available data on this. Likewise, the contribution of cytochrome P450 enzyme action to vinorelbine metabolism has potential implications in patients receiving other drugs metabolized by this route .

Metabolism

Metabolism of vinorelbine appears to be hepatic. All metabolites of vinorelbine are formed by the CYP3A4 isoform of cytochromes P450, except 4-O-deacetylvinorelbine which is likely to be formed by carboxylesterases.
4-O-deacetylvinorelbine is the only active metabolite and the main one observed in blood. Excretion is mainly by the biliary route (18.5
% appears in the urine).

Properties of Vinorelbine

alpha  D20 +52.4° (c = 0.3 in CHCl3)
Density  1.36±0.1 g/cm3(Predicted)
storage temp.  Store at 4°C, protect from light
solubility  >25.9mg/mL in DMSO
form  Powder
pka 11.36±0.60(Predicted)

Safety information for Vinorelbine

Signal word Danger
Pictogram(s)
ghs
Skull and Crossbones
Acute Toxicity
GHS06
ghs
Health Hazard
GHS08
GHS Hazard Statements H301:Acute toxicity,oral
H315:Skin corrosion/irritation
H319:Serious eye damage/eye irritation
H341:Germ cell mutagenicity
Precautionary Statement Codes P260:Do not breathe dust/fume/gas/mist/vapours/spray.
P280:Wear protective gloves/protective clothing/eye protection/face protection.

Computed Descriptors for Vinorelbine

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