title: Phase I and pharmacokinetic evaluations of UFT plus oral leucovorin.
abstract: The phase I development program of tegafur and uracil (UFT) in the United States has included evaluation of the drug as a single agent and subsequent studies of its biochemical modulation by oral leucovorin. Phase I trials of single-agent UFT examined both a 5-day schedule repeated every 21 days and a 28-day schedule repeated every 35 days. In all of the trials the total dose was divided by three and administered three times daily at 8-hour intervals. Like intravenous schedules of fluorouracil (5-FU), UFT has schedule-dependent toxicity, with granulocytopenia being the dose-limiting toxicity for the 5-day regimen and diarrhea being the dose-limiting toxicity for the 28-day regimen. The suggested phase II doses for UFT administered without leucovorin were 800 mg/m2/day for the 5-day schedule and 360 mg/m2/day for the 28-day schedule. Subsequent phase I studies combining UFT with oral leucovorin used a 28-day schedule repeated every 35 days. Diarrhea was the dose-limiting toxicity, and the recommended phase II dose was UFT, 300 mg/m2/day, plus leucovorin, 90 mg/day. Pharmacokinetic evaluation showed that single-dose UFT results in maximum plasma levels and an area under the concentration-time curve that increased with escalating UFT doses. In addition, 5-FU levels were detectable throughout the 28-day dosing period; however, there was no evidence of significant accumulation of uracil, tegafur, or 5-FU. The administration of leucovorin in this trial provided continuous exposure of d,l-leucovorin and 5-methyltetrahydrofolate with little variation between doses or days.
authors.affiliation: University of Texas, M. D. Anderson Cancer Center, Houston, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pazdur
mesh_terms: D000284:Administration, Oral; D000931:Antidotes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D017321:Clinical Trials, Phase I as Topic; D004338:Drug Combinations; D005472:Fluorouracil / Q000008:administration & dosage / Q000097:blood; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D005641:Tegafur / Q000008:administration & dosage / Q000493:pharmacokinetics; D013763:Tetrahydrofolates / Q000097:blood; D014498:Uracil / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000931:Antidotes; D004338:Drug Combinations; D013763:Tetrahydrofolates; C096910:UFT(R) drug; D005641:Tegafur; D014498:Uracil; D002955:Leucovorin; C005984:5-methyltetrahydrofolate; D005472:Fluorouracil