Plasma and cerebrospinal fluid pharmacokinetics of gemcitabine after intravenous administration in nonhuman primates

Purpose: Gemcitabine (dFdC) is a difluorine-substituted deoxycytidine analogue that has demonstrated antitumor activity against both leukemias and solid tumors. Pharmacokinetic studies of gemcitabine have been performed in both adults and children but to date there have been no detailed studies of its penetration into cerebrospinal fluid (CSF). The current study was performed in nonhuman primates to determine the plasma and CSF pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine (dFdU) following i.v. administration. Methods. Gemcitabine, 200 mg/kg, was administered i.v. over 45 min to four nonhuman primates. Serial plasma and CSF samples were obtained prior to, during, and after completion of the infusion for determination of gemcitabine and dFdU concentrations. Gemcitabine and dFdU concentrations were measured using high-performance liquid chromatography (HPLC) and modeled with model-dependent and model-independent methods. Results. Plasma elimination was rapid with a mean t(1/2) of 8 +/- 4 min (mean +/- SD) for gemcitabine and 83 +/- 8 min for dFdU. Gemcitabine total body clearance (Cl-TB) was 177 +/- 40 ml/min per kg and the Vd(ss) was 5.5 +/- 1.0 l/kg. The maximum concentrations (C-max) and areas under the time concentration curves (AUC) for gemcitabine and dFdU in plasma were 194 +/- 64 muM and 63.8 +/- 14.6 muM.h, and 783 +/- 99 muM and 1725 +/- 186 muM.h, respectively. The peak CSF concentrations of gemcitabine and dFdU were 2.5 +/-1.4 muM and 32 +/- 41 muM, respectively. The mean CSF:plasma ratio was 6.7% for gemcitabine and 23.8% for dFdU. Conclusions. There is only modest penetration of gemcitabine into the CSF after i.v. administration. The relatively low CSF exposure to gemcitabine after i.v. administration suggests that systemic administration of this agent is not optimal for the treatment of overt leptomeningeal disease. However, the clinical spectrum of antitumor activity and lack of neurotoxicity after systemic administration of gemcitabine make this agent an excellent candidate for further studies to assess the safety and feasibility of intrathecal administration.