Gemcitabine is a fluorine deoxycitidine analog that has shown clinical activity against several solid tumor including ovarian cancer, pancreatic cancer and in non-small-cell lung cancer (NSCLC) when combined with cisplatin (DDP). Gemcitabine is a pro-drug that requires for its activity, intracellular activation to triphosphate form (dFdCTP). Gemcitabine is rapidly deactivated in plasma by cytidine deaminase to 2’,2’-difluorodeoxycitidine (dFdU). Previous studies demonstrated that the achievement of a threshold value of plasma concentration of Gemcitabine superior to 10 μM is crucial to obtain intracellular accumulation of dFdCTP. Prolonged infusion of Gemcitabine at fixed dose rate (FDR) of 10 mg/m2/min compared with standard 30min infusion are able to maintain for a longer period the above mentioned critical plasma concentration, increasing at maximal levels the rate of accumulation of the active metabolite dFdCTP. In order to evaluate the pharmacological profile of Gemcitabine administered as FDR infusion in NSCLC patients treated in combination with DDP, we designed a dose-finding and pharmacokinetic study. Gemcitabine was administered at FDR of 10 mg/m2/min at doses ranging between 600 and 1200 mg/m2 on day 1 and 8, with 75 mg/m2 of DDP on day 8. Blood samples were collected on day 1 and 8 during the infusions and up to 24 hours. Drug and dFdU plasma levels were determined by HPLC/MS/MS (LOQ 10 ng/ml). Pharmacokinetic results obtained in 22 patients revealed that DDP does not affect Gemcitabine pharmacokinetics. The target plasma concentration of 10μM was achieved in 70% of the 12 patients treated with 600-900 mg/m2 (range 10.1-17.5 μM), but surprisingly in only 40% of the 10 patients treated with 1000-1200 mg/m2 (range 7.5-12.7 μM). These data were in accord with the observation made after 3 cycles, that the majority of the responses (8/13) were obtained with the dose 600-900 mg/m2 and that the treatment was well tolerated even at the higher doses of 1000-1200 mg/m2. Further pharmacokinetic studies that involve also the measure of dFdCTP are in progress to define the optimal schedule of Gemcitabine administration as FDR infusion. (Partially supported by Eli Lilly Italia).

[Proc Amer Assoc Cancer Res, Volume 45, 2004]