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

Abstract

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.

Clinical Pharmacokinetics of Paclitaxel Monotherapy: An Updated Literature Review

“…A number of population pharmacokinetic models have described the pharmacokinetics of paclitaxel monotherapy and have provided important insight into paclitaxel pharmacokinetics and pharmacodynamics. Hempel et al [97] estimated the total paclitaxel plasma CL to be 6.7 L/h for 13 predominantly male patients treated with 20-50 mg/m 2 as a 1-h infusion. This is in agreement with the reported values for non-compartmental analyses of higher doses of paclitaxel.…”

“…Six population pharmacokinetic studies of paclitaxel monotherapy were identified [96][97][98][99][100][101] and these are Table 2. Briefly, all but one of the studies had dense sampling with study populations ranging from seven to 150 individuals.…”

Synergistic Anti-glioma Effects <i>in Vitro</i> and <i>in Vivo</i> of Enediyne Antibiotic Neocarzinostatin and Paclitaxel <i>via</i> Enhanced Growth Delay and Apoptosis-Induction

“…Heimans et al 24) reported that PTX may not cross the intact BBB, but its concentrations in the tumor tissue were in the therapeutic range, in which the BBB disruption or leakage of brain tumor may partially facilitate the PTX penetration. [25][26][27] Many investigations revealed that the combination of PTX with other effective chemotherapeutic drugs, RNA interference or immunotherapy could improve anti-glioma efficacy in vitro and in vivo. [28][29][30] The fundamental challenge to the discovery of microtubule-targeting drugs may be mainly attributed to the drug resistance.…”