Multicenter phase II study of weekly oral vinorelbine for stage IV non-small-cell lung cancer.

Vokes, Everett E.; Rosenberg, Richard K.; Jahanzeb, Mohammed; Craig, Jesse C.; Gralla, Richard J.; Belani, Chandra P.; Jones, Stephen E.; Bigley, Joseph; Hohneker, John

doi:10.1200/jco.1995.13.3.637

Cited by 37 publications

(7 citation statements)

References 15 publications

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“…Influence of food for patients who had received prior radiation therapy [52] [53] published a report on the activity and safety of oral vinorelbine. As recommended in the Phase I dose-finding study, the first step used a weekly dose of 80 mg/m 2 .…”

Section: 2002mentioning

confidence: 99%

Oral versus intravenous vinorelbine: clinical safety profile

Gebbia¹,

Puozzo²

2005

Expert Opinion on Drug Safety

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The availability of chemotherapeutic drugs administrable by oral route represents a step forward in the management of cancer patients. Among oral agents, vinorelbine is particularly interesting for its pharmacological characteristics and clinical efficacy. Oral vinorelbine is rapidly absorbed (1.5-3 hours) with an elimination half-life of approximately 40 hours. It shows a low level of binding to plasma proteins (13%), is highly bound to platelets (78%) and has a hepatic metabolism and an absolute bioavailability of 40% with a moderate and similar interpatient variability for the two forms. Food has no influence on the pharmacokinetic profile of oral vinorelbine even if nausea/vomiting is less frequent and less severe in the fed patients than in the fasting patients. Therefore, to ensure patient comfort, it is recommended that oral vinorelbine is administered with a snack. All the metabolites of oral vinorelbine have been identified and, among these, only deacetyl-vinorelbine presented activity demonstrating that for both oral and intravenous (i.v.) routes of administration the drug has the same metabolism pattern. Oral vinorelbine is eliminated mainly in a unconjugated form via the bile. In this process, the CYP 3A4 isoform of cytochrome P450 is mostly involved. Absorption of oral vinorelbine is not delayed in elderly patients. After oral administration, blood concentrations of vinorelbine in elderly patients are within the range of values observed in younger patients. The absolute bioavailability is close to 38% in elderly whereas it is close to 40% in younger patients. This difference is not significant. As compared to the intravenous drug, oral vinorelbine demonstrated linear pharmacokinetics as well an absolute bioavailability of approximately 40%, and a reliable dose-correspondence of 80 mg/m2 oral form --> 30 mg/m2 i.v. and 60 mg/m2 oral --> 25 mg/m2 i.v. Therefore, i.v. and oral forms show similar interindividual variability, same metabolism pattern, reproducible intra-patient blood exposure, and same pharmacokinetic-pharmacodynamic relationship. Oral vinorelbine has shown significant activity in advanced non-small cell lung cancer. Given at 60 mg/m2/week for the first 3 administrations and then increased to 80 mg/m2/week achieved the same efficacy as i.v. vinorelbine in terms of progression-free survival, overall survival, objective response. Mild-to-moderate gastrointestinal toxicity, easily manageable with standard treatment was recorded. Reproducible efficacy compared to previously reported results with vinorelbine i.v. Also, in advanced breast cancer, oral vinorelbine has shown significant activity with a good therapeutic index. Albeit no formal comparison between the oral and the intravenous formulations of vinorelbine has been made, however, the oral route seems to offer major advantages to patients who are faced with a clear decrease in the frequency of hospital admissions as compared to that needed to give intravenous chemotherapy.

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Section: 2002mentioning

confidence: 99%

Oral versus intravenous vinorelbine: clinical safety profile

Gebbia¹,

Puozzo²

2005

Expert Opinion on Drug Safety

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“…Several randomised studies suggested that monotherapy with Paclitaxel, Docetaxel, Vinorelbine or Gemcitabine might be a convenient alternative for patients with a bad performance status, leading to a significant increase in survival compared to BSC [29][30][31] and to a better control of tumour-related symptoms combined with improved quality of life [29][30][31][32]. Another attractive perspective for palliative treatment is the new oral application of Vinorelbine which was active in stage-IV NSCLC and showed comparable efficacy to intravenous Vinorelbine in a randomised trial [33,34].…”

Section: Two Drugs Versus One Drug Monotherapymentioning

confidence: 99%

Chemotherapy in stage-IV NSCLC

Reck

Gatzemeier

2004

Lung Cancer

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“…L 59] Even with this positive pharmacokinetic data, the development of a powder-filled formulations was stopped because of the risk to workers inhaling Orally administered vinorelbine has been studied in 162 patients with non-small-cell cancer recei ving dosage rangi ng from 50 to 100 mg/m-" week. [62] The pharmacokinetics were also investigated in 57 patients who had blood samples collected corresponding (theoretically) to peak concentration times (I and 2 hours after administration). The plasma concentration estimated by HPLC showed a wide interpatient variability with values ranging from nondetectable to 124 ug/L at 1 hour)62]…”

Section: Absorptionmentioning

confidence: 99%

Clinical Pharmacokinetics of Vinorelbine

Levêque¹,

Jehl²

1996

Clinical Pharmacokinetics

110

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Vinorelbine (5'-noranhydrovinblastine) is a recently developed semisynthetic anticancer drug which belongs to the Catharanthus alkaloid family. Its mechanism of action is only partially known but it is assumed that it acts, like vinblastine and vincristine, as an antimicrotubule agent arresting cell division in mitosis. Clinically, vinorelbine has mainly shown activity in the treatment of advanced non-small-cell lung cancer and the treatment of metastatic breast cancer. Early pharmacokinetic data were obtained with radioactive assays (radio-immunoassay or 3H-labelled vinorelbine), then with more selective high performance liquid chromatographic techniques. Vinorelbine is usually administered intravenously but there has also been some experimentation with an oral formulation. The bioavailability of a liquid filled gelatin capsule ranges between 12 and 59% with a mean value of 27% [standard deviation (SD) 12%]. Vinorelbine is rapidly absorbed with peak serum concentration reached within 2 hours. In vitro, vinorelbine is mainly distributed into the blood cells, especially platelets (78%) and lymphocytes (4.8%) The unbound blood fraction is around 2%. In lung tissue vinorelbine concentrations are much higher than in serum, by up to 300-fold 3 hours after administration. Little is known about the biotransformation of vinorelbine. Desacetylvinorelbine is considered to be a minor metabolite and is only found in urine fractions, representing 0.25% of the injected dose. Urinary excretion of vinorelbine is low, accounting for less than 20% of the dose. Faecal elimination has been demonstrated in 2 patients who were administered 3H-labelled vinorelbine; the amount of radioactivity recovered in the faeces was 33.9 and 58.4% for the 2 patients, respectively. The pharmacokinetic profile of vinorelbine is often described as a 3-compartment model characterised by a long terminal half-life (t1/2) that varies between 20 and 40 hours and a large apparent volume of distribution (Vd) of around 70 L/kg. Systemic clearance ranges between 72.54 and 89.46 L/h (1209 and 1491 ml/min) when determined by high performance liquid chromatography and is higher than that reported by radioimmunoassay [46.2 L/h (770 ml/min)]. This could be due to the greater specificity of the chromatographic method. Vinorelbine has been administered by continuous intravenous infusion over 4 days. Steady-state was reached and the concentrations obtained were above the in vitro IC50 (concentration of drug causing 50% inhibition). The effect of liver disease on vinorelbine pharmacokinetics has been studied in patients with breast cancer. Patients with massive secondary liver disease had a lower systemic clearance than those who have no liver disease or a lesser invasion. In children, vinorelbine seems to display a shorter t1/2 (14.7 hours) than that found in adults. In addition, the systemic clearance is highly variable [from 12 to 93.96 L/h/m2 (200 to 1566 ml/min/m2)]. Vinorelbine is often co-administered with cisplatin in the treatment of advanced non-small-cell lu...

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Multicenter phase II study of weekly oral vinorelbine for stage IV non-small-cell lung cancer.

Cited by 37 publications

References 15 publications

Oral versus intravenous vinorelbine: clinical safety profile

Oral versus intravenous vinorelbine: clinical safety profile

Chemotherapy in stage-IV NSCLC

Clinical Pharmacokinetics of Vinorelbine

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