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 metabolite, difluorodeoxycytidine triphosphate (dFdCTP), suggested that small increases in peak intracellular dFdCTP levels would have a profound effect on its intracellular area under the curve (AUC). Previous studies had shown that a dose rate of 10 mg/m²/min that achieved plasma gemcitabine concentrations of 15-20 μmol/l maximized the intracellular rate of accumulation of dFdCTP. This phase I study was therefore designed to evaluate the clinical feasibility of this pharmacologically-based strategy; assessing the toxic effects and anticancer activity of high weekly doses of gemcitabine administered at a fixed dose rate of 10 mg/m²/min. Patients and methods: Thirty one patients with solid tumor malignancies received 103 courses of gemcitabine. Twenty nine patients had received prior treatment. Weekly doses were escalated from 1200 mg/m² administered intravenously over 120 minutes to 2800 mg/m² over 280 minutes for three weeks every four weeks, Results: The first-course MTD was 2250 mg/m². The dose limiting toxicity was myelosuppression with thrombocytopenia and granulocytopenia quantitatively more important than anemia. However, cumulative myelosuppression was documented suggesting that a lower MTD of 1800 mg/m² was more appropriate with a recommended phase II starting dose of 1500 mg/m². There was no neurologic toxicity. Nonhematologic toxicity was minimal and included fatigue, nausea, and skin rash, but was not dose dependent. Three objective responses were documented. Conclusions: Escalated doses of gemcitabine designed to maximize intracellular dFdCTP levels can be safely administered using a fixed dose rate. The encouraging anticancer effects documented in patients with refractory malignancies suggests that short gemcitabine infusions based on well-established cellular pharmacologic principles may improve the therapeutic index of this agent. Comparison with Standard 30-minute bolus driving will be evaluated in subsequent randomized phase II trials.