Pharmacokinetics of gemcitabine in a patient with end-stage renal disease: effective clearance of its main metabolite by standard hemodialysis treatment

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Abstract
Gemcitabine (2',2'-difluorodeoxycytidine) is a cytotoxic agent with a low toxicity profile and proven activity against a number of solid tumors. It is not known whether gemcitabine is safe to administer to patients with kidney failure, and if dose adjustment is necessary. We determined the tolerability and pharmacokinetics of gemcitabine and its noncytotoxic metabolite 2',2'-difluorodeoxyuridine (dFdU) in a patient with end-stage renal disease on maintenance hemodialysis therapy. A 64-year-old patient with pancreatic cancer and end-stage renal disease received two cycles of gemcitabine at a standard dose of 1000 mg/m(2) given as a 30-min infusion on days 1 and 10. A regular 3.5-h hemodialysis treatment was performed 24 h after each infusion. Plasma and dialysate concentrations of gemcitabine and dFdU were determined by HPLC. The tolerability of gemcitabine treatment was assessed by clinical and laboratory parameters. For gemcitabine, the maximal plasma concentration, terminal half-life (t(1/2)) and area under the concentration-time curve (AUC) were similar to those reported for patients with normal renal function. In contrast, end-stage renal disease resulted in a five- to tenfold prolongation of terminal half-life and a distinct increase in the AUC of plasma dFdU in this patient. Plasma dFdU was effectively eliminated by hemodialysis treatment. Both cycles of gemcitabine were tolerated well with no unexpected side effects observed. Gemcitabine treatment in end-stage renal disease with intermittent standard hemodialysis treatment is safe and well tolerated. The pharmacokinetic data suggest that dose adjustment of gemcitabine should be avoided to ensure its full cytotoxic activity, and that hemodialysis treatment should be initiated 6-12 h after its administration to minimize the potential side effects of the metabolite dFdU.