Population pharmacokinetics of short intravenous vinorelbine infusions in patients with metastatic breast cancer

Purpose. To develop a population pharmacokinetic model of vinorelbine administered by short intravenous infusion in metastatic breast cancer patients. Methods. Vinorelbine was administered as infusions of 5-10 min at 15, 20 or 25 mg/m(2) to 30 patients. Blood samples were collected over 18 h. Plasma concentrations of vinorelbine were determined by HPLC. Population pharmacokinetic analysis was performed using a nonlinear mixed effects modeling method. Results. Vinorelbine concentration-time profiles were best described by a three-compartment open model. Plasma clearance (CL) was high and positively related to lean body weight (LBW) and body surface area (BSA) or to a combination of height and body weight (BW). Elevated serum alkaline phosphatases had a negative effect on CL. Typical population estimates of CL and central distribution volume (V-1) were 74.2 l/h and 7.8 l, respectively. The interindividual population coefficients of variation for CL and V-1 were 17.0% and 32.0%, respectively. The stability and predictive performance of the final population pharmacokinetic model were assessed using 200 bootstrap samples of the original data. Conclusion. This study identified combined effects of BSA and serum alkaline phosphatases on clearance. These results partly support the conventional dose adjustment of vinorelbine based on BSA, but suggest dose modification in cases of extreme values of serum alkaline phosphatases.