Administering gemcitabine as fixed-dose-rate infusion in combination with cisplatin, potentially effective target plasma concentrations are achieved in patients with advanced non-small cell lung cancer

The fluorine deoxycitidine analogue gemcitabine has shown clinical activity against several solid tumors 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 transformation 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 15 µM is essential to obtain intracellular accumulation of dFdCTP. Prolonged infusion of gemcitabine at fixed dose rate (FDR) of 10 mg/m2/min compared with standard 30 minutes 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 assess the achievement of the target concentration with prolonged infusion, we evaluated the pharmacokinetic of gemcitabine in 8 patients with NSCLC participating to a dose-finding and pharmacokinetic study. Gemcitabine was administered by an electronic pump to maintain a fixed infusion rate of 10 mg/m2/min at doses of 600 or 1200 mg/m2 on day1 (D1) and (D8), with 75 mg/m2 of DDP on D8. For pharmacokinetic evaluation, blood samples were collected on these days performing a total of 32 courses, during the infusions and up to 24 hours. Drug and dFdU plasma levels were determined by a validated HPLC/MS/MS method. Pharmacokinetic results showed that all patients and at each courses achieved the steady state concentration during the infusion, being the gemcitabine half-life lower than 30 minutes. The study demonstrated that the target plasma concentration of 15 µM was successfully achieved in all courses of the patients treated with 600 mg/m2 (range D1: 20.2-25.8 µM; D8: 16.9-28.2 µM ) and in 14/16 of those treated with 1200 mg/m2 (range D1: 17.1-64.2 µM; D8: 15-39.8 µM). In only two occasions were achieved concentrations of 12.5 and 12.6 µM. DDP did not affect gemcitabine pharmacokinetics. In addition, the measure of the intracellular dFdCTP by HPLC is in progress in the WBC of the treated patients and the results will be presented. In conclusion this study suggests that FDR infusion is able to provide the patients with plasma concentration in the therapeutic target range of 15µM.