title: Pharmacokinetic and biochemical analysis in the treatment of weekly paclitaxel in relapsed breast cancer.
abstract: The mechanism(s) by which weekly paclitaxel exerted more therapeutic efficacy than the triweekly schedule in relapsed breast cancer is still unclear. To assess the rationale in therapeutic efficacy of weekly paclitaxel in relapsed breast cancer, pharmacokinetic and biochemical analyses were examined in terms of the mean peak plasma concentration at 0 min (Cmax), 30 min, and 24 h after finishing the infusion, and the extracellular domain of HER-2 in response to the treatment with paclitaxel. Twenty-five patients treated with weekly 1 h infusion of paclitaxel in the dose range from 40 mg/m(2) to 80 mg/m(2) were studied. Eleven patients responded to the treatment including 4 cases of complete response (CR) and 7 cases of partial response (PR), while 14 patients did not respond including 12 cases of no change (NC) and 2 cases of progressive disease (PD). The plasma concentration of paclitaxel and extracellular domain of HER-2 in the patients were measured by high-pressure liquid chromatography and enzyme immunoassay, respectively. The peak concentration (Cmax) and the other peaks at 30 min and 24 h in 10 patients including 3 cases of 40 mg/m(2), 3 cases of 60 mg/m(2) and 4 cases of 80 mg/m(2) in the weekly paclitaxel were compared in proportion to the increase of dose escalation, and compared to their tumor response. Further, the plasma levels of extracellular domain of HER-2 in 17 patients treated with the weekly paclitaxel were measured, and also compared to their tumor response. The mean Cmax treated with 40 mg/m(2), 60 mg/m(2) and 80 mg/m(2) in the weekly paclitaxel was 1.94, 2.18 and 1.54 microM, respectively. The dose escalation of paclitaxel and the dose intensity were not correlated with the increase of plasma concentration of paclitaxel nor with the tumor response. In contrast, the plasma level of extracellular domain of HER-2 in responders was higher than that of non-responders in the weekly paclitaxel regimen(p=0.0512, Mann-Whitney's U-test). These results suggest that tumor response to the weekly 1 h infusion of paclitaxel was not associated with the plasma concentration and the dose intensity, rather the plasma level of extracellular domain of HER-2 protein may be a predictor of tumor response in the treatment of weekly paclitaxel in relapsed breast cancer.
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. rkim@ipc.hiroshima-u.ac.jp
authors.forename: R
authors.initials: R
authors.lastname: Kim
authors.forename: A
authors.initials: A
authors.lastname: Osaki
authors.forename: T
authors.initials: T
authors.lastname: Toge
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel / Q000493:pharmacokinetics*; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases