Clinical results of a pharmacodynamically-based strategy for higher dosing of gemcitabine in patients with solid tumors.
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 mumol/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.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.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.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 dosing will be evaluated in subsequent randomized phase II trials.
Touroutoglou, N; Gravel, D; Raber, MN; Plunkett, W; Abbruzzese, JL
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