title: Prolonged infusion of gemcitabine: clinical and pharmacodynamic studies during a phase I trial in relapsed acute myelogenous leukemia.
abstract: OBJECTIVE
  To determine the maximum tolerated duration of infusions at the fixed gemcitabine dose rate of 10 mg/m(2)/min and to analyze the pharmacodynamic actions in leukemia blasts during gemcitabine therapy.
  
  
  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/m(2)/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 micromol/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.
  
  
  CONCLUSIONS
  At the fixed-dose rate of 10 mg/m(2)/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.
authors.affiliation: Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. vgandhi@mdanderson.org
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: Min
authors.initials: M
authors.lastname: Du
authors.forename: Mary
authors.initials: M
authors.lastname: Ayres
authors.forename: Elihu H
authors.initials: EH
authors.lastname: Estey
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D004247:DNA / Q000096:biosynthesis; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D004247:DNA; D000093542:Gemcitabine