title: Pharmacokinetics of gefitinib predicts antitumor activity for advanced non-small cell lung cancer.
abstract: BACKGROUND
  We assessed the relationship between the plasma concentration of gefitinib and its efficacy in Japanese patients with advanced non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Plasma trough levels of gefitinib were measured on days 3 (D3) and 8 (D8) by high-performance liquid chromatography in 44 patients with advanced NSCLC treated with 250 mg gefitinib daily. Eligibility criteria included performance status < or =3, age < or = 80 years, and stages IIIB-IV cancer. Epidermal growth factor receptor mutations in 23 patients were analyzed retrospectively.
  
  
  RESULTS
  The median plasma gefitinib values were 662 ng/ml on D3 and 1064 ng/ml on D8, and the D8/D3 ratio was 1.587. The median progression-free survival (PFS) was 71 days, and the median overall survival was 224 days. Adenocarcinoma, never smoking, and high D8/D3 ratio were associated with better PFS. Multivariate analysis showed that PFS was associated with never smoking and high D8/D3 ratio. Never-smokers with a high D8/D3 ratio showed the best PFS. Overall survival was not associated with the D8/D3 ratio. Epidermal growth factor receptor mutation analysis of 23 patients showed that 15 patients had exon 19 deletion and/or exon 21 point mutation. Median PFS was similar between mutation-positive and mutation-negative individuals in the high D8/D3 group, whereas mutation-negative individuals in the low D8/D3 group showed the worst median PFS.
  
  
  CONCLUSIONS
  A high D8/D3 ratio was independently associated with better PFS in patients with NSCLC treated with gefitinib. Our findings suggest that the pharmacokinetics of gefitinib may be involved in its antitumor activity.
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki, Japan. yi-nakamu@umin.ac.jp
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Soda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takatani
authors.forename: Minoru
authors.initials: M
authors.lastname: Fukuda
authors.forename: Seiji
authors.initials: S
authors.lastname: Nagashima
authors.forename: Tomayoshi
authors.initials: T
authors.lastname: Hayashi
authors.forename: Mikio
authors.initials: M
authors.lastname: Oka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsukamoto
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011799:Quinazolines / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077156:Gefitinib