A pharmacokinetic study of gemcitabine at fixed dose rate infusion in patients with impaired hepatic function

12009 Background: The aim of this study was to evaluate if hepatic dysfunction leads to increased toxicity of gemcitabine (gem) at fixed dose rate, and to characterize the pharmacokinetic (PK) of gem and its major metabolite (2`,2`-difluorodeoxyuridine- 2dFdU) in patients (pts) with normal and altered liver function. Methods: Eight pts with metastatic pancreatic or biliary tract cancer were treated with the followed schedule: gem 1000 mg/m2 at 10/mg/m2/min fixed rate days 1,8, and 15 every 28 days for a maximum of six cycles. Three pts had normal serum bilirubin level and AST level less than two times the upper limit of normal (ULN) (Cohort I); four pts had bilirubin level from 1.6 to 7.0 mg/dL and normal AST level, one pt had serum bilirubin level less than 1.6 mg/dL and AST level greater than two times the ULN (Cohort II). The PK parameters measured were: plasmatic peak concentration (Cmax), area under the plasma concentration-time curve (AUCexp), total plasma clearance (Cl p) and half life (t1/2). Results: Patient characteristics were: median age 62 yrs (range 28–75), male/female 4/4, median cycles cohort I: 6 cycles (3–6), median cycles cohort II: 3 cycles (1–5), median follow-up: 30 weeks (range 3–79) and median weeks of treatment: 14 (1–25). The rate of dose reduction was the same in the two cohorts, as the rate of omitted administrations. Patients with liver dysfunction tolerated gemcitabine without increased toxicity and neither AST nor bilirubin elevation was observed after drug administration. PK parameters were calculated at the first cycle and the results are presented below (see table ). Conclusions: The pharmacokinetics of gemcitabine at fixed dose rate in patients with impaired liver function seems similar to control; no difference between the two cohorts was observed in terms of toxicity and dose reduction. [Table: see text] No significant financial relationships to disclose.