title: Pharmacokinetics of Weekly Paclitaxel and Feasibility of Dexamethasone Taper in Japanese Patients with Advanced Non-small Cell Lung Cancer.
abstract: OBJECTIVE
  Weekly paclitaxel combined with a platinum-based agent has been advocated as an alternative regimen for patients with advanced non-small cell lung cancer (NSCLC). Limited studies exist on the tolerability of weekly paclitaxel in Japanese patients with advanced NSCLC. Furthermore, the feasibility of dexamethasone taper in the premedication regimen for weekly paclitaxel has not been examined in these patients. To address this issue, we assessed the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of weekly paclitaxel in Japanese patients with advanced NSCLC in a dose-escalation Phase I trial and examined the feasibility of dexamethasone taper in these patients.
  
  
  METHODS
  Weekly 1-hour infusions of paclitaxel were administered at doses of 80 to 120 mg/m(2) (dose escalation of 20 mg/m(2)). The 7-week treatment cycle consisted of 6 infusions followed by a 2-week treatment interval. Pharmacokinetics were assessed during the first cycle. Dexamethasone was commenced at 16 mg and doses were successively halved if hypersensitivity reactions were absent.
  
  
  RESULTS
  A total of 15 patients with either Stage IIIB or IV NSCLC were enrolled. Although no dose-limiting toxicity was observed at 120 mg/m(2), 4 of 6 patients with peripheral neuropathy required discontinuation of treatment. The maximum accepted dose and the recommended dose were 120 and 100 mg/m(2), respectively. No grade ≥3 adverse events were observed at 100 mg/m(2). The maximum drug concentration and AUC correlated with dose escalation. The pharmacokinetic parameters after the first and sixth infusions were similar, indicating that repeated administration of paclitaxel did not result in drug accumulation or affect its pharmacokinetic profile. Partial response was observed in 3 of 15 patients. Plasma adrenocorticotropic hormone and cortisol levels decreased during treatment but approached baseline levels after a dexamethasone-free interval.
  
  
  CONCLUSIONS
  Weekly paclitaxel at 100 mg/m(2) given as a 1-hour infusion for 6 weeks followed by a 2-week treatment interval was well tolerated by Japanese patients with advanced NSCLC. Dexamethasone taper was feasible in these patients, and no clear trend in plasma adrenocorticotropic hormone or cortisol levels was observed.
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. Electronic address: hnokihar@ncc.go.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.affiliation: Discovery Medicine & Clinical Pharmacology Japan, Bristol-Myers K.K., Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Hiraoka
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D003907:Dexamethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced
chemical_list: D003907:Dexamethasone; D017239:Paclitaxel
keywords: dexamethasone; paclitaxel; pharmacokinetics; phase I; safety