Pharmacokinetics of gemcitabine at fixed-dose rate infusion in patients with normal and impaired hepatic function

Autor: Andrea Sacconi, Barbara Nuvoli, Michele Milella, Simona Colantonio, M. Contestabile, Alessandra Felici, Susanna Di Segni, Gennaro Citro, Francesco Cognetti, Isabella Sperduti, Massimo Zaratti
Rok vydání: 2009
Předmět:
Male
Antimetabolites
Gastroenterology
Deoxycytidine
chemistry.chemical_compound
Liver Function Tests
Tandem Mass Spectrometry
Medicine
Pharmacology (medical)
Prospective Studies
Prospective cohort study
Infusions
Intravenous
Chromatography
High Pressure Liquid
Chromatography
medicine.diagnostic_test
Liver Diseases
Middle Aged
Antineoplastic
Biliary Tract Neoplasms
High Pressure Liquid
Area Under Curve
Toxicity
Female
Drug
Intravenous
medicine.drug
Adult
medicine.medical_specialty
Infusions
Antimetabolites
Antineoplastic
Bilirubin
medicine.drug_class
Adenocarcinoma
Antimetabolite
Drug Administration Schedule
Dose-Response Relationship
Pharmacokinetics
Internal medicine
Humans
Aged
Pharmacology
Dose-Response Relationship
Drug
business.industry
Gemcitabine
Pancreatic Neoplasms
Endocrinology
chemistry
Liver function
business
Liver function tests
Floxuridine
Zdroj: ResearcherID
ISSN: 0312-5963
Popis: Background and objectives: 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. Patients and 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/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. Conclusion: 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.
Databáze: OpenAIRE
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