title: Pharmacokinetic parameters of gefitinib predict efficacy and toxicity in patients with advanced non-small cell lung cancer harboring EGFR mutations.
abstract: OBJECTIVE
  The relationship between plasma concentration and antitumor activity of gefitinib was assessed in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations.
  
  
  METHODS
  Plasma trough levels of gefitinib were measured on days 2 (D2) and 8 (D8) by high-performance liquid chromatography in 31 patients. Plasma concentrations of gefitinib were also measured 10 h after the first administration in 21 of these patients to calculate the elimination half-life of gefitinib.
  
  
  RESULTS
  The median trough levels were: 197 ng/ml 10 h from the first administration of gefitinib; 113 ng/ml on D2; and 358 ng/ml on D8. The median D8/D2 ratio was 2.709, and the median elimination half-life was 15.7 h. The median progression-free survival (PFS) was 273 days, and the median overall survival (OS) was 933 days. A high D8/D2 ratio was significantly correlated with better PFS, though the plasma trough levels on D2 and D8 were not significantly related to PFS. The elimination half-life was not a significant factor for PFS, but it was significantly correlated with high-grade adverse events. Pharmacokinetic parameters were not significantly correlated with OS.
  
  
  CONCLUSIONS
  A high D8/D2 ratio, but not elimination half-life, might be a predictor of better PFS in patients with NSCLC harboring EGFR mutations treated with gefitinib. On the other hand, long elimination half-life was related to high-grade adverse events in these patients. Clinical Trial Registration UMIN000001066.
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.|Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mizoguchi
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan. yi-nakamu@umin.ac.jp.|Department of Medical Oncology, Division of Thoracic Oncology, Tochigi Cancer Center, 4-9-13 Yohnan, Utsunomiya, Japan. yi-nakamu@umin.ac.jp.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Drug Metabolism and Disposition, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sano
authors.affiliation: Clinical Research Center, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Drug Metabolism and Disposition, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Ikegami
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Motoshima
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Takemoto
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Ogawara
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Senju
authors.affiliation: Department of Respiratory Medicine, Nagasaki Prefecture Shimabara Hospital, Shimabara, Japan.
authors.forename: Nanae
authors.initials: N
authors.lastname: Sugasaki
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Nakatomi
authors.affiliation: Clinical Oncology Center, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Fukuda
authors.affiliation: Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Izumikawa
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mukae
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006207:Half-Life; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Chemotherapy; EGFR mutations; Elimination half-life; Gefitinib; Non-small cell lung cancer; Pharmacokinetics