title: Phase I dose-finding and pharmacokinetic study of docetaxel and gefitinib in patients with advanced or metastatic non-small-cell lung cancer: evaluation of drug-drug interaction.
abstract: OBJECTIVE
  Docetaxel and gefitinib play key roles in the treatment of non-small-cell lung cancer (NSCLC), and their combination could be of interest. Both drugs are mainly metabolized by CYP3A4, and drug-drug interactions are a major concern. This phase I dose-finding study was designed to assess the tolerability and drug-drug interactions in this combination using full pharmacokinetic (PK) samplings.
  
  
  METHODS
  Docetaxel was intravenously administered on days 1 and 22 at a dose of 45 or 60 mg/m(2). Gefitinib (250 mg/day) was orally administrated starting on day 2. Ten PK samplings of docetaxel were performed on days 1 and 22. Seven PK samplings of gefitinib were performed on day 18 ± 3 and on day 22.
  
  
  RESULTS
  Twelve patients with advanced or metastatic NSCLC were enrolled without considering EGFR mutation status. The major toxicity was neutropenia. Two patients withdrew from this study due to dose-limiting toxicities; however, the toxicity profiles in this combination were generally acceptable. The docetaxel AUC0-24 and C max did not differ whether administered alone or with gefitinib, and the geometric mean ratios (GMRs) of AUC0-24 and C max (co-administrated/administrated alone) were 0.95 (90 % CI 0.85-1.06) and 0.95 (90 % CI 0.85-1.05), respectively. Furthermore, the GMRs of the steady state gefitinib AUC0-24 and C max were 0.93 (90 % CI 0.84-1.03) and 0.98 (90 % CI 0.88-1.09), respectively.
  
  
  CONCLUSIONS
  The tolerability of 60 mg/m(2) docetaxel with 250 mg/day gefitinib was confirmed, and we observed no drug-drug interaction in this combination.
authors.affiliation: Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan.|Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Motonaga
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, Japan. nbryamam@ncc.go.jp.|Department of Experimental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan. nbryamam@ncc.go.jp.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Makino
authors.affiliation: Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Ando-Makihara
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.affiliation: Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Mikihisa
authors.initials: M
authors.lastname: Takano
authors.affiliation: Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005500:Follow-Up Studies; D000077156:Gefitinib; D006207:Half-Life; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D010352:Patient Dropouts; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; D000077156:Gefitinib
keywords: Docetaxel; Drug–drug interaction; Gefitinib; Non-small-cell lung cancer; Phase I study