CLINICAL-RESULTS OF A PHARMACODYNAMICALLY-BASED STRATEGY FOR HIGHER DOSING OF GEMCITABINE IN PATIENTS WITH SOLID TUMORS

Background: The long intracellular half-life of gemcitabine's active m etabolite, difluorodeoxycytidine triphosphate (dFdCTP), suggested that small increases in peak intracellular dFdCTP levels would have a prof ound effect on its intracellular area under the curve (AUC), Previous studies had shown that a dose rate of 10 mg/m(2)/min that achieved pla sma gemcitabine concentrations of 15-20 mu mol/l maximized the intrace llular rate of accumulation of dFdCTP. This phase I study was therefor e designed to evaluate the clinical feasibility of this pharmacologica lly-based strategy; assessing the toxic effects and anticancer activit y of high weekly doses of gemcitabine administered at a fixed dose rat e of IO mg/m(2)/min. Patients and methods: Thirty one patients with so lid tumor malignancies received 103 courses of gemcitabine. Twenty nin e patients had received prior treatment. Weekly doses were escalated f rom 1200 mg/m(2) administered intravenously over 120 minutes to 2800 m g/m(2) over 280 minutes for three weeks every four weeks. Results: The first-course MTD was 2250 mg/m(2). The dose-limiting toxicity was mye losuppression with thrombocytopenia and granulocytopenia quantitativel y more important than anemia. However, cumulative myelosuppression was documented suggesting that a lower MTD of 1800 mg/m(2) was more appro priate with a recommended phase II starting dose of 1500 mg/m(2). Ther e was no neurologic toxicity. Nonhematologic toxicity was minimal and included fatigue, nausea: and skin rash, but was not dose dependent. T hree objective responses were documented. Conclusions: Escalated doses of gemcitabine designed to maximize intracellular dFdCTP levels can b e safely administered using a fixed dose rate. The encouraging antican cer effects documented in patients with refractory malignancies sugges ts that short gemcitabine infusions based on well-established cellular pharmacologic principles may improve the therapeutic index of this ag ent. Comparison with standard 30-minute bolus dosing will be evaluated in subsequent randomized phase II trials.