Population pharmacokinetics of low-dose paclitaxel in patients with brain tumors

Our aim was to assess the pharmacokinetics of a low-dose schedule of paclitaxel in combination with radiation therapy in patients with brain tumors. Eighteen patients received 20-50 mg/m2 paclitaxel as a 1-h infusion 18-24 h before radiation with 2 Gy on 5 consecutive days. In total, 156 plasma samples from 13 patients and 38 urine samples from nine patients were collected and analyzed by a validated capillary electrophoresis method. Data analysis was done using NONMEM with a two-compartmental model and proportional error model. No signs of non-linearity in the pharmacokinetic parameters were observed in this dosing range. The median cumulative urinary excretion was 2.4% (range 0.86-7.72%) of the given dose. Plasma clearance was found to be 6.71 l/h+/-70% and central volume of distribution was 3.64 l+/-79% (population mean +/- interindividual variability, respectively). At the time of the radiation, i.e. 24 h after administration with the lowest dose of 20 mg/m2, the mean concentration of paclitaxel was 0.038 mg/l (0.045 microM) in plasma. We conclude that even with the lowest dose of 20 mg/m2 paclitaxel, plasma concentrations at the time of radiation are achieved which are radiosensitizing in vitro.