title: Plasma and pleural fluid pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with non-small-cell lung cancer with pleural effusion.
abstract: BACKGROUND
  Erlotinib is orally active and selectively inhibits the tyrosine kinase activity of the epidermal growth factor receptor. The pleural space penetration and exposure of erlotinib is poorly understood. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in non-small-cell lung cancer (NSCLC) of malignant pleural effusion (MPE).
  
  
  METHODS
  We analyzed the PK of erlotinib and OSI-420 on days 1 and 8 after beginning erlotinib therapy in 9 patients with MPE. Their concentrations were determined by high-performance liquid chromatography with ultraviolet detection. Blood samples were obtained five times per day: before administration, and 2, 4, 8, and 24 hours after administration. Pleural effusions were obtained once per day, 2 hours after administration on day 1, and before administration on day 8. The exceptions were cases 2 and 4, which had pleural effusions obtained just before drug administration, and 2, 4, 8, and 24 hours after administration.
  
  
  RESULTS
  The mean percentage of penetration from plasma to pleural effusion for erlotinib was 18% on day 1 and 112% on day 8, while these values for OSI-420 were 9.5% on day 1 and 131% on day 8. The area under the drug concentration-time curve of pleural fluid for erlotinib was 28,406 ng-hr/mL for case 2 and 45,906 ng-hr/mL for case 4.
  
  
  CONCLUSIONS
  There seems to be a significant accumulation of both erlotinib and OSI-420 in MPE with repeated dosing. Although larger studies will be necessary to determine the true impact of erlotinib MPE accumulation on plasma PK and safety, erlotinib can be administered safely to patients with MPE with respect to efficacy and side effects.
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan. masago@kuhp.kyoto-u.ac.jp
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Masago
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Togashi
authors.forename: Masahide
authors.initials: M
authors.lastname: Fukudo
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Terada
authors.forename: Kaoru
authors.initials: K
authors.lastname: Irisa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sakamori
authors.forename: Young Hak
authors.initials: YH
authors.lastname: Kim
authors.forename: Tadashi
authors.initials: T
authors.lastname: Mio
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Inui
authors.forename: Michiaki
authors.initials: M
authors.lastname: Mishima
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010996:Pleural Effusion / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013997:Time Factors
chemical_list: C487471:OSI-420; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride