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Prolonged Infusion of Gemcitabine: Clinical and Pharmacodynamic Studies During a Phase I Trial in Relapsed Acute Myelogenous Leukemia

From the Departments of Experimental Therapeutics and Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Varsha Gandhi, PhD, Department of Experimental Therapeutics, Box 71, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: vgandhi{at}mdanderson.org

PURPOSE: To determine the maximum tolerated duration of infusions at the fixed gemcitabine dose rate of 10 mg/m²/min and to analyze the pharmacodynamic actions in leukemia blasts during gemcitabine therapy.

PATIENTS AND METHODS: The study was conducted in a phase I trial by escalating the duration of gemcitabine infusion at a fixed-dose rate of 10 mg/m²/min. Patients with relapsed or refractory acute myelogenous leukemia (AML) received gemcitabine for 8.0 (n = 3), 10.0 (n = 3), 12.5 (n = 8), 15.5 (n = 3), or 18.0 hours (n = 2). Pharmacokinetic and pharmacodynamic investigations were undertaken in circulating AML blasts.

RESULTS: Gemcitabine was infused for up to 18 hours at the fixed-dose rate. Four patients had grade 3 toxicities at longer infusion schedules. One patient had a partial remission; two others had a reduction in blasts and concomitant rise in neutrophils. Gemcitabine triphosphate was detectable in AML cells even at 1 hour after the start of infusion in eight patients. The concentration ranged from 130 to 900 µmol/L at the end of the infusion. Consistently, there was a rapid decline in DNA synthesis, which remained suppressed at 85% to 95% during and for at least 10 hours after the end of the infusion. Compared with levels in cells measured before therapy, at 8 hours after the start of the infusion, there was a decline in the cellular purine deoxynucleotide pools.

CONCLUSION: At the fixed-dose rate of 10 mg/m²/min, gemcitabine could be administered for longer than 12 hours without untoward toxicity. The favorable toxicity profile and pharmacokinetic and pharmacodynamic features warrant combination with DNA-damaging agents.

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