title: Association of pharmacokinetics and pharmacogenomics with safety and efficacy of gefitinib in patients with EGFR mutation positive advanced non-small cell lung cancer.
abstract: OBJECTIVE
  Gefitinib is a potent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and is a key drug for patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). The pharmacokinetics of orally administered gefitinib varies greatly among patients. We prospectively evaluated the association of pharmacokinetics and pharmacogenomics with the safety and efficacy of gefitinib in patients with EGFR mutation-positive advanced NSCLC.
  
  
  METHODS
  Pharmacokinetics was evaluated with samples of peripheral blood obtained on day 1 before treatment and 1, 3, 5, 8, and 24h after gefitinib (250 mg per day) was administered and on days 8 and 15 as the trough values. The plasma concentration of gefitinib was analyzed with high-performance liquid chromatography. The genotypes of ABCG2, ABCB1, CYP3A4, CYP3A5, and CYP2D6 genes were analyzed with direct sequencing.
  
  
  RESULTS
  The subjects were 35 patients (21 women; median age, 72 years; range, 53 to 90 years) with stage IV adenocarcinoma harboring EGFR mutations. The median peak plasma concentration (Cmax) was 377 (range, 168-781)ng/mL. The median area under the curve (AUC) of the plasma concentration of gefitinib from 0 to 24h was 4893 (range, 698-13991) ng/mL h. The common adverse events were skin toxicity (68% of patients), diarrhea (46%), and liver injury (63%). One patient died of drug-induced interstitial lung disease (ILD). The overall response rate was 82.9% (95% confidence interval, 66.4%-93.4%). The median progression-free survival time was 10 months, and the median survival time was 25 months. The pharmacokinetics and pharmacogenomics were not associated with significantly different toxicities, response rates, or survival times with gefitinib. However, the AUC and Cmax were highest and the trough value on day 8 was the second highest in one patient who died of drug-induced ILD.
  
  
  CONCLUSIONS
  Elevated gefitinib exposure might be associated with drug-induced ILD.
authors.affiliation: Depatment of Respirology, National Hospital Organization, Tokyo National Hospital, Kiyose, Tokyo, Japan; Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Kiyose, Tokyo, Japan. Electronic address: thirose-shw@umin.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirose
authors.affiliation: Institute of Molecular Oncology, Showa University, Kiyose, Tokyo, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Kiyose, Tokyo, Japan.
authors.forename: Sojiro
authors.initials: S
authors.lastname: Kusumoto
authors.affiliation: Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Kiyose, Tokyo, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Oki
authors.affiliation: Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Kiyose, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Murata
authors.affiliation: Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Kiyose, Tokyo, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Sugiyama
authors.affiliation: Division of Medical Oncology, Showa University School of Medicine, Shinagawa, Tokyo, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Ishida
authors.affiliation: Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Kiyose, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Shirai
authors.affiliation: Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Kiyose, Tokyo, Japan.
authors.forename: Masanao
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Institute of Molecular Oncology, Showa University, Kiyose, Tokyo, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Yamaoka
authors.affiliation: Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Kiyose, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Okuda
authors.affiliation: Institute of Molecular Oncology, Showa University, Kiyose, Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Ohmori
authors.affiliation: Division of Medical Oncology, Showa University School of Medicine, Shinagawa, Tokyo, Japan.
authors.forename: Yasutsuna
authors.initials: Y
authors.lastname: Sasaki
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016903:Drug Monitoring; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010597:Pharmacogenetics; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics*; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Gefitinib; Interstitial lung disease; Pharmacogenomics; Pharmacokinetics