Abstract 2747: Prediction of neutropenia in patients with solid tumor by population pharmacokinetics / pharmacodynamics analyses for the different formulations of paclitaxel
Authors: Hironobu Minami, Tomohide Tamura, Yasuhiro Fujiwara, Yasutsuna Sasaki, Hidetoshi Yamaya, Katsuhiro Ono
Journal: Cancer Research (2010)

Abstract Background: Neutropenia is one of the main toxicities of paclitaxel. In a population pharmacokinetics/pharmacodynamics (PPK/PD) analysis, the pharmacokinetic profile of paclitaxel concentration and the time course of neutrophil counts were correlated. Nanoparticle albumin-bound (nab)-paclitaxel is a novel Cremophor-free formulation of paclitaxel, with pharmacokinetics that are dose-proportional within the clinical dose ranges. A higher dose of nab-paxlitaxel (260 mg/m2) is recommended, while 175 mg/m2 of solvent-based (sb) -paclitxel has been used for the treatment of breast cancer. In a phase III study comparing the two drug formulations, response rate and time-to progression were superior in the nab-paclitaxel arm. To compare the pharmacokinetics and the time course of neutrophil counts after administration of either nab-paclitaxel or sb-paclitaxel., PPK/PD analyses were performed using the data of Japanese cancer patients. Method: Eighty-four Japanese patients with advanced solid tumors were treated; 27 with nab-paclitaxel at doses ranging from 80 to 300 mg/m2 over 30 minutes (include weekly regimen) and the others by sb-paclitaxel from 105 to 270 mg/m2 over 3 hours with every 3 weeks regimen. The plasma concentration of paclitaxel was analyzed by a PPK approach using a non-linear three compartment model with Michaelis-Menten processes for sb-paclitaxel, while a linear three compartment model was used for nab-paclitaxel. For PPK/PD analyses, the time courses of neutrophil counts were analyzed using semi-physiological models consisting of transit compartments with individual PK parameters estimated by the PPK models using software, NONMEM ver. VI. Results: Predicted clearance of paclitaxel by PPK at a recommended dose of nab-paclitaxel given every three weeks for breast cancer (260 mg/m2) was higher than that of sb-paclitaxel at a commonly used dose of 175mg/m2 (21.9 vs 10.5 L/hr/m2). The volume of distribution was 697 vs 235 L/m2, respectively, for nab-paclitaxel and sb-paclitaxel. Those differences could be attributed to paclitaxel entrapment to Cremophor micelle in plasma. In the PPK/PD analyses, Median neutrophil nadir was roughly estimated 1300 /mm3 at 10 days for nab-paclitaxel and 640 /mm3 at 11 days for sb-paclitaxel. Population estimates for PD model parameters of nab-paclitaxel were comparable to those estimated for sb-paclitaxel; the drug stimulus parameter as cytotoxic effect, which directly related to plasma concentration for sb-paclitaxel (4.10 [µg/ml]−1), was similar to that for nab-paclitaxel (4.51 [µg/ml]−1). Conclusion: Despite the higher clearance and volume of distribution for nab-paclitaxel in comparison with those for sb-paclitaxel, the PD parameters estimated and the time-courses of neutrophil count were similar for both formulations when they were given at respective recommended doses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2747.