Bayesian pharmacokinetic estimation of vinorelbine in non-small-cell lung cancer patients

Sabot, Christophe; Marquet, Pierre; Debord, Jean; Carpentier, Nicolas; Merle, Louis; Lachâtre, Gérard

doi:10.1007/s002280050441

Cited by 21 publications

(11 citation statements)

References 17 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: 79%

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: 79%

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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“…No previous report has defined, on a large number of patients, the extent to which demographic variables or other covariates could influence the disposition of vinorelbine. Only two analyses have been performed and on a small number of patients ( n ≤12) to either establish a limited sampling strategy [27] or to examine the effect of age on vinorelbine pharmacokinetics [28]. Such approaches did not yield a relevant population model because of the relatively high interpatient variability on clearance and volume of distribution.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics model and limited sampling strategy for intravenous vinorelbine derived from phase I clinical trials

Nguyen

Tranchand

Puozzo

et al. 2002

Brit J Clinical Pharma

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Aims a) To characterize the pharmacokinetics of intravenous vinorelbine, b) to use a population analysis for the identification of patient covariates that might appreciably influence its disposition and c) to define a limited sampling strategy for further Bayesian estimation of individual pharmacokinetic parameters. Methods All data were collected from 64 patients (99 courses) entered in three different phase I trials that have been previously reported. All patients received vinorelbine as a 20 min infusion with dose levels ranging from 20-45 mg m x2 . The population pharmacokinetic model was built in a sequential manner on a subset of two-thirds of the data, starting with a covariate-free model then progressing to a covariate model using the nonlinear-mixed effect methodology. The remaining onethird of the data were used to validate several sparse sampling designs.Results A linear three-compartment model characterized vinorelbine blood concentrations (n=1228). Two primary pharmacokinetic parameters (total clearance and volume of distribution) were related to various combinations of covariates. The relationship for total clearance (CL total (l h x1 )=29.2rBSAr(1x0.0090 Plt)+ 6.7rWt/Cr s ) was dependent on the patient's body surface area (BSA), weight (Wt), serum creatinine (Cr s ) and platelet count before administration (Plt). The optimal limited sampling strategy consisted of a combination of three measured blood concentrations; the first immediately before the end of infusion or 20 min later, the second at either 1 h, 3 h or 6 h and the third at 24 h after drug administration.Conclusions A population pharmacokinetic model and a limited sampling strategy for intravenous vinorelbine have been developed. This is the first population analysis performed on the basis of a large phase I database that has identified clinical covariates influencing the disposition of i.v. vinorelbine. The model can be used to obtain accurate Bayesian estimates of pharmacokinetic parameters in situations where extensive pharmacokinetic sampling is not feasable.

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Bayesian pharmacokinetic estimation of vinorelbine in non-small-cell lung cancer patients

Abstract: We demonstrated that Bayesian estimation allows, at minimal cost and minimal disturbance for the patient, the determination of several vinorelbine pharmacokinetic parameters and therefore dose adaptation from as few as two drug concentrations, measured at 6 h and 24 h after infusion.

Cited by 21 publications

References 17 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

Population pharmacokinetics model and limited sampling strategy for intravenous vinorelbine derived from phase I clinical trials

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