title: Pharmacokinetics of gemcitabine at fixed-dose rate infusion in patients with normal and impaired hepatic function.
abstract: OBJECTIVE
  Gemcitabine (2,2-difluorodeoxycytidine [dFdC]) can be administered in a standard 30-minute infusion or in a fixed-dose-rate (FDR) infusion to maximize the rate of accumulation of triphosphate, its major intracellular metabolite. The standard 30-minute infusion requires dose adjustment in patients with organ dysfunction, especially in patients with elevated baseline serum bilirubin levels. On the other hand, the FDR infusion is burdened by increased haematological toxicity. The primary aim of this study was to evaluate the pharmacokinetics of dFdC and its metabolite difluorodeoxyuridine (dFdU) in patients with normal and impaired hepatic function.
  
  
  METHODS
  In this prospective study, patients with pancreatic or biliary tract carcinoma and normal or impaired hepatic function tests were considered eligible for recruitment. Patients were recruited according to the following criteria: (i) serum bilirubin <1.6 mg/dL and AST and ALT <2 times the upper the limit of normal (ULN) [cohort I]; and (ii) serum bilirubin >1.6 mg/dL and/or AST/ALT >2 times the ULN (cohort II). An FDR infusion of gemcitabine 1000 mg/m2 was administered on days 1, 8 and 15 every 4 weeks. The pharmacokinetic analysis of gemcitabine and dFdU was performed with high-performance liquid chromatography-tandem mass spectrometry assay in cycles 1 and 2.
  
  
  RESULTS
  Thirteen patients were enrolled, four in cohort I and nine in cohort II. All patients were assessable for toxicity and pharmacokinetic analysis. The grade and rate of toxicities were similar in both groups, and patients with elevation of bilirubin and/or transaminases did not require dose reduction of gemcitabine. Pharmacokinetic analysis revealed a reduction of the experimental area under the plasma concentration-time curve for gemcitabine and dFdU in patients with hepatic dysfunction when compared with patients with normal hepatic function. All other pharmacokinetic parameters were similar in the two cohorts. No statistical difference was demonstrated for all parameters evaluated between cycle 1 and cycle 2 in the two groups.
  
  
  CONCLUSIONS
  Gemcitabine 1000 mg/m2 can be administered as an FDR infusion in patients with altered hepatic function without causing additional toxicity compared with patients with normal hepatic function.
authors.affiliation: Laboratory of Pharmacokinetics, Regina Elena Cancer Institute, Rome, Italy. alefelici@yahoo.it
authors.forename: Alessandra
authors.initials: A
authors.lastname: Felici
authors.forename: Susanna
authors.initials: S
authors.lastname: Di Segni
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.forename: Simona
authors.initials: S
authors.lastname: Colantonio
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.forename: Barbara
authors.initials: B
authors.lastname: Nuvoli
authors.forename: Michela
authors.initials: M
authors.lastname: Contestabile
authors.forename: Andrea
authors.initials: A
authors.lastname: Sacconi
authors.forename: Massimo
authors.initials: M
authors.lastname: Zaratti
authors.forename: Gennaro
authors.initials: G
authors.lastname: Citro
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
mesh_terms: D000230:Adenocarcinoma / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001661:Biliary Tract Neoplasms / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005467:Floxuridine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D008107:Liver Diseases / Q000097:blood* / Q000150:complications / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D011446:Prospective Studies; D053719:Tandem Mass Spectrometry; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D005467:Floxuridine; D003841:Deoxycytidine; C084565:2',2'-difluoro-2'-deoxyuridine; D000093542:Gemcitabine