Phase I and pharmacokinetic study of oral UFT, a combination of the 5-fluorouracil prodrug tegafur and uracil

• Published in: Clinical cancer research 1996-09, Vol.2 (9), p.1461-1467
• Main Authors: MUGGIA, F. M, WU, X, SPICER, D, GROSHEN, S, JEFFERS, S, LEICHMAN, C. G, LEICHMAN, L, CHAN, K. K
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Area Under Curve; Biological and medical sciences; Chemotherapy; Cohort Studies; Diarrhea - chemically induced; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Fatigue - chemically induced; Female; Fluorouracil - pharmacokinetics; Fluorouracil - therapeutic use; Humans; Male; Medical sciences; Middle Aged; Nausea - chemically induced; Pharmacology. Drug treatments; Prodrugs - administration & dosage; Prodrugs - adverse effects; Prodrugs - pharmacokinetics; Tegafur - administration & dosage; Tegafur - adverse effects; Tegafur - pharmacokinetics; Tegafur - therapeutic use; Uracil - administration & dosage; Uracil - adverse effects; Uracil - pharmacokinetics; Uracil - therapeutic use; Vomiting - chemically induced
• ISSN: 1078-0432; 1557-3265

UFT is an oral preparation combining the 5-fluorouracil (FU) prodrug tegafur (FT) and uracil (U) in a 1:4 ratio, which is commercially available in Japan for the treatment of breast and gastrointestinal cancers. We sought to determine the tolerance of daily oral UFT and to relate this tolerance to the pharmacokinetics of FT and/or the derived FU, while exploring the possibility of circadian FU kinetics contributing to the results. A 28-day schedule followed by 2 weeks rest was began at the initial level of 300 mg/m2/day administered either at 8 a.m. or at 6 p.m. At the following level, 400 mg/m2/day patients were randomly assigned to a split-dose administration or to the above single, timed dose administration. Intolerance to single dosing was clearly demonstrated, and only the split dosing was advanced to 500 mg/m2/day. When this level proved too toxic, 400 mg/m2 was studied further on a 7 a.m., 3 p.m., and 11 p.m. (every 8 h) schedule. Pharmacology was determined on selected patients. In the single dose administration, areas under the curves of FU were higher following p.m. dosing, although substantial interpatient variation was present. Toxicities (diarrhea and neutropenia) were more severe in patients receiving the drug in single daily doses. We conclude that the kinetics of FT are saturable, with disproportionate increases in area under the curve (and toxicities) as dose levels are increased. With divided dosing, tolerance improves. UFT at a dose of 400 mg/m2/day administered as three divided doses (every 8 h) is suitable for Phase II studies, although toxicity requiring cessation of drug administration prior to completion of 28-day cycles will occur in some patients.