Pharmacokinetics of vinorelbine in man

Marquet, Pierre; Lachâtre, Gérard; Debord, Jean; Eichler, B; Bonnaud, F; Nicot, G

doi:10.1007/bf00314866

Cited by 48 publications

(15 citation statements)

References 6 publications

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“…The PK of pemetrexed and vinorelbine were consistent with data obtained with single-agent chemotherapy (Marquet et al, 1992;Leveque and Jehl, 1996;Sabot et al, 1998). There was no evidence for PK interaction between the two drugs.…”

Section: Discussionsupporting

confidence: 80%

Pemetrexed pharmacokinetics and pharmacodynamics in a phase I/II study of doublet chemotherapy with vinorelbine: implications for further optimisation of pemetrexed schedules

Rivory

Clarke

2007

Br J Cancer

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The purpose of this study was to investigate the utility of plasma pharmacokinetic and pharmacodynamic measures including plasma deoxynucleosides, homocysteine and methylmalonic acid concentrations in understanding the time course and extent of the inhibition of thymidylate synthase (TS) by pemetrexed in the context of a phase I/II combination study with vinorelbine. Eighteen patients received supplementation with folic acid and Vitamin B 12 1 week before beginning treatment with pemetrexed and vinorelbine administered in a dose-escalating manner on a 21-day cycle. Heparinised blood samples were collected from consenting patients in the first cycle for pharmacokinetic analyses and in the first two cycles for determination of plasma thymidine, deoxyuridine, homocysteine and methylmalonic acid concentrations. These values were correlated with response and toxicity. Plasma deoxyuridine was used as a measure of TS inhibition, and concentrations of deoxyuridine were significantly elevated relative to baseline on days 1 (Po0.01), 2 (Po0.001) and 3 (Po0.05) after treatment at all pemetrexed dose levels (400 -700 mg m À2 ). The magnitude of deoxyuridine elevation correlated with pemetrexed area under the plasma concentration -time curve (AUC) (r 2 ¼ 0.23, Po0.05). However, deoxyuridine concentrations returned to baseline between 8 and 15 days after treatment with pemetrexed, suggesting that inhibition of TS was not durable. Pemetrexed AUC correlated with the percentage decline (relative to baseline) in both platelets (r 2 ¼ 0.58, Po0.001) and leucocytes (r 2 ¼ 0.26, Po0.05) at day 8. Baseline homocysteine was also significantly correlated with these measures of haematological toxicity (r 2 ¼ 0.37, Po0.01 and r 2 ¼ 0.39, Po0.01, respectively). In addition, there was a significant reduction of plasma homocysteine on days 8 (Po0.005) and 15 (Po0.05) in cycle 1 compared to baseline values. The results suggest that the TS inhibitory effects of pemetrexed are short-lived and make the case for a more frequent schedule of administration such as every 2 weeks. The lack of protracted TS inhibition may be due to concomitant vitamin administration, and this may be the mechanism by which vitamins prevent life-threatening toxicity from pemetrexed. Baseline homocysteine concentration remains a predictive marker for haematological toxicity even following folate supplementation.

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Section: Discussionsupporting

confidence: 80%

Pemetrexed pharmacokinetics and pharmacodynamics in a phase I/II study of doublet chemotherapy with vinorelbine: implications for further optimisation of pemetrexed schedules

Rivory

Clarke

2007

Br J Cancer

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“…In our study, systemic exposure was lower at a given dose compared with that reported in previous adult studies but was proportionate to clearance. The calculated area under the plasma concentration-time curve in this study at 30 mg/m 2 was 676 ng/mL-h compared with 800 to 900 ng/mL-h reported in adult patients (19,20). Thus, we believe that a weekly schedule of i.v.…”

Section: Discussionmentioning

confidence: 39%

Phase I Evaluation of Oral and Intravenous Vinorelbine in Pediatric Cancer Patients: A Report from the Children's Oncology Group

Johansen¹,

Kuttesch

Bleyer

et al. 2006

Clinical Cancer Research

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Purpose: Vinorelbine (Navelbine) is an orally absorbable Vinca with broad antitumor activity.It differs from other Vinca in that it is structurally modified on the catharanthine nucleus and has differential actions on tubulin that render it less neurotoxic than other compounds in this class.We conducted a phase I study of vinorelbine given the activity of Vinca alkaloids in many pediatric tumors. Experimental Design: We evaluated the safety and pharmacokinetics of oral and i.v. vinorelbine administered weekly Â 6 in children (age, 2-17 years) with different tumors. Patients with disease involvement in the bone marrow were eligible but were stratified and dose-escalated separately. Oral vinorelbine (week 1) was administered as liquid-filled gelatin capsules at thrice the i.v. dose. Intravenous vinorelbine doses of 24 to 37.5 mg/m 2 were administered on weeks 2 to 6. Results: The dose-limiting toxicity in patients without marrow involvement was reversible neutropenia. Common nonhematologic toxicities included V grade 2 nausea/vomiting and increased hepatic transaminases. A higher mean i.v. Cl TB was observed (1.75 F 1.0 L/h/kg) compared with adult reports, with a mean t 1/2B of 16.5 F 9.7 hours. Mean oral bioavailability was 28.5 F 22.5%. The apparent oral clearance (12.1 F13.0 L/h/kg) and volume of distribution (69.4 F 30.6 L/kg) were substantially higher than in adults given similar oral doses. Conclusions:The maximum tolerated dose in children without bone marrow involvement was 30 mg/m 2 , similar to that reported in adults, with myelosuppression being the dose-limiting toxicity. Higher plasma clearance resulted in lower area under the plasma concentration-time curves at a given dose compared with that reported in adults.

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“…4,5 The elimination half-life after intravenous administration is 42 to 45 hours and 24 to 56 hours after oral administration. 5,6 Pharmacokinetics in elderly patients (older than 65 years) is similar to those reported in younger people. 7 This report reviews the most important studies involving Vinorelbine in ABC with particular regard to the results of randomized trials in order to evaluate its role in this subset of patients.…”

Section: Introductionsupporting

confidence: 55%

A Review of Vinorelbine in the Treatment of Advanced Breast Cancer

Brunello

Roma

Basso

et al. 2009

Clinical Medicine. Therapeutics

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Abstract:Vinorelbine is a semi-synthetic vinca alkaloid that has been shown active in many tumor types and is currently registered for the treatment of advanced breast cancer (ABC) and non-small cell lung cancer (NSCLC), and it is used in other cancer type such as prostate cancer, lymphomas, gynecologic malignancies. This agent has a generally favorable safety profile, and may be suitable for use in special populations such as the elderly and/or frail patient. However, with the taxanes established as standard second line treatment for ABC after failure of an anthracycline, Vinorelbine has been generally relegated for use as third line therapy, in competition with the oral compound Capecitabine. Combination regimens of Vinorelbine and Gemcitabine have been indeed widely studied, and have been demonstrated to be safe and effective. More recently, the exciting results observed with the combination of Vinorelbine and Trastuzumab in patients with Her-2 overexpressing tumors, as well as the development of a reliable formulation and revised schedule of oral Vinorelbine appear to have revived the interest in this compound in the management of this disease. Yet, data from properly designed randomized clinical trials are eagerly awaited to confirm the amount of available data which are mostly based on phase II studies.

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Pharmacokinetics of vinorelbine in man

Cited by 48 publications

References 6 publications

Pemetrexed pharmacokinetics and pharmacodynamics in a phase I/II study of doublet chemotherapy with vinorelbine: implications for further optimisation of pemetrexed schedules

Pemetrexed pharmacokinetics and pharmacodynamics in a phase I/II study of doublet chemotherapy with vinorelbine: implications for further optimisation of pemetrexed schedules

Phase I Evaluation of Oral and Intravenous Vinorelbine in Pediatric Cancer Patients: A Report from the Children's Oncology Group

A Review of Vinorelbine in the Treatment of Advanced Breast Cancer

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