By means of the simultaneous analysis of oral and intravenous data the bioavailability (F=36%) and its associated variability were estimated. At usual doses similar levels of variability were observed between oral and intravenous routes. As a result of the identification of covariates from phase I data and their confirmation from phase II data further explorations based on limited sampling strategies are now possible. The use of a simultaneous oral/intravenous model allows a better characterization of the PK profile of vinorelbine after administration by either vascular or oral route

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.

The effects of food on the pharmacokinetics and safety profile of a soft-gel capsule formulation of vinorelbine (Navelbine Oral) were evaluated in fed and fasted patients with solid tumours or lymphomas. A group of 18 patients (12 planned) were entered into a multicentre phase I pharmacokinetic study following a crossover design with a 1-week wash-out period. Patients received the first dose of 80 mg/m(2) oral vinorelbine either after fasting or after ingestion of a standard continental breakfast. The second dose of 80 mg/m(2) was administered 1 week later in the alternate feeding condition to the first dose. Of the 18 patients, 13 were eligible for pharmacokinetic evaluation. The mean time to maximum concentration (T(max)) was shorter in fasted patients (1.63+/-0.98 h in blood, 1.67+/-0.96 h in plasma) than in fed patients (2.48+/-1.40 h in blood, 2.56+/-1.65 h in plasma) but these differences are not likely to modify the safety and/or efficacy of oral vinorelbine. Values for C(max) and AUC were similar in fed and fasted patients and no significant differences were observed. The safety profile of oral vinorelbine observed in this limited number of patients appears to be comparable to that usually reported for vinorelbine, the main toxicity being neutropenia. Only one episode of febrile neutropenia was reported. The main nonhaematological toxicities encountered were gastrointestinal, consisting of nausea, vomiting, diarrhoea and constipation. A tendency for a lower incidence of vomiting was suggested when oral vinorelbine was administered after a standard breakfast. Based on this study, the administration of oral vinorelbine to fasted patients is not mandatory since administration after a standard breakfast does not lead to differences in body exposure to the drug. As the comfort of patients may be improved when the treatment is administered after a light meal, this procedure can be recommended in clinical practice.

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