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

Abstract

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.

A Phase I Dose-Escalating and Pharmacokinetic Study of Docetaxel and Vinorelbine as First-Line Chemotherapy for Metastatic Breast Cancer

“…Moreover, a significantly decreased vinorelbine plasma clearance was reported when docetaxel infusion was immediately followed by a 10-min intravenous vinorelbine bolus in comparison with the inverse sequence (106 and 216 l/h, respectively) [14]. However, mean values of both vinorelbine blood clearance and docetaxel plasma clearance were consistent with those previously reported for single-agent chemotherapy (39.4 [9] and 36.8 l/h [10], respectively). Then, pharmacokinetic interaction was not likely to occur in this schedule.…”

“…The mean docetaxel and vinorelbine clearance (i.e. 24.5 and 23.8 l/h/m 2 , respectively) are similar to previously reported values [10, 11]. Of note, the patient who had fever in cycle 1 (i.e.…”

“…area under the curve, AUC, of blood or plasma concentrations versus time for vinorelbine and docetaxel, respectively) according to limited sampling strategies published previously. Vinorelbine data of the present study were added to a database of 64 patients and analyzed according to a linear three-compartment model [9]. For docetaxel concentrations, prior information for bayesian estimation was provided by population pharmacokinetic parameters obtained from 547 patients using a linear three-compartment model without any covariate [10].…”

A simultaneous oral/intravenous population pharmacokinetic model for vinorelbine

“…Intravenous vinorelbine has been approved and marketed in many countries since 1989 for non-small-cell lung cancer and advanced breast cancer. To identify the main sources of variability in vinorelbine after IV administration a previous population PK analysis was carried out in 64 phase I patients (n=99 PK data sets) [6]. An interpatient variability of 30% (expressed in CV) and intrapatient variability of 10% in total clearance were determined.…”

Oral Vinorelbine and Cisplatin with Concomitant Radiotherapy in Stage III Non-Small Cell Lung Cancer (NSCLC): A Feasibility Study

“…Oral vinorelbine is effective in NSCLC but exerts slightly higher gastrointestinal toxicity. Crossover studies assessing the bioavailability of oral and intravenous vinorelbine [19] showed that an oral dose of 80 mg/m 2 resulted in similar exposure as the intravenous dose of 30 mg/m 2 and that the oral dose of 60 mg/m 2 is comparable to the intravenous dose of 25 mg/m 2 which is the dose commonly used in combination regimens [20]. Therefore, we decided to define the highest level in this phase I trial as a dose of oral vinorelbine of 60 mg/m 2 and to initiate the trial with a lower dose of 40 mg/m 2 corresponding to approximately to 15 mg/m 2 of intravenous vinorelbine and escalate the dose over a total of 3 levels.…”