title: The effect of different etiologies of hepatic impairment on the pharmacokinetics of gefitinib.
abstract: OBJECTIVE
  We investigated whether the pharmacokinetics and tolerability of gefitinib were altered in patients with hepatic impairment due to cirrhosis or hepatic metastases in two open, parallel-group, multicenter studies.
  
  
  METHODS
  In Study 1, subjects with normal hepatic function or mild, moderate, or severe hepatic impairment (Child-Pugh criteria) due to cirrhosis received single-dose gefitinib 250 mg (n = 10 per group). In Study 2, patients with solid malignant tumors with normal liver biochemistry (n = 18), moderate (n = 16), or severe (n = 7) hepatic impairment (liver biochemistry tests) due to metastases received gefitinib 250 mg daily for 28 days.
  
  
  RESULTS
  In Study 1, the geometric mean area under the plasma concentration-time curve (AUC) for gefitinib was significantly higher in patients with hepatic impairment compared with healthy subjects; hepatic impairment was associated with reduced gefitinib plasma clearance, longer half-life, and reduced plasma metabolite levels. In Study 2, the geometric mean gefitinib steady-state AUC during the 24-h dosing interval was slightly, but not significantly, higher in patients with moderate hepatic impairment; there were, however, no significant differences between groups in gefitinib and metabolite pharmacokinetic parameters. In both studies, gefitinib was well tolerated across all cohorts.
  
  
  CONCLUSIONS
  We conclude that the effect of hepatic impairment on gefitinib pharmacokinetics depends on the underlying etiology of that impairment and its classification.
authors.affiliation: Third Faculty of Medicine, Charles University and Faculty Hospital, Kralovske Vinohrady, Prague, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Horak
authors.forename: Jeff
authors.initials: J
authors.lastname: White
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Mark
authors.initials: M
authors.lastname: Verrill
authors.forename: James
authors.initials: J
authors.lastname: Carmichael
authors.forename: Alison
authors.initials: A
authors.lastname: Holt
authors.forename: Mireille
authors.initials: M
authors.lastname: Cantarini
authors.forename: Merran
authors.initials: M
authors.lastname: Macpherson
authors.forename: Alan
authors.initials: A
authors.lastname: Swaisland
authors.forename: Helen
authors.initials: H
authors.lastname: Swaisland
authors.forename: Chris
authors.initials: C
authors.lastname: Twelves
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077156:Gefitinib