title: High inter- and intrapatient variation in 5-fluorouracil plasma concentrations during a prolonged drug infusion.
abstract: The purpose of the study was to examine inter- and intrapatient variation in 5-fluorouracil (5-FU) plasma concentrations in adult cancer patients receiving a 3-day drug infusion. Fourteen patients received 1266 mg/m2 N-(phosphonacetyl)-L-aspartate (PALA) infused i.v. over 15 min on day 1, followed immediately by a loading dose of 500 mg/m2 calcium leucovorin over 30 min. Then a prolonged infusion of leucovorin at 500 mg/m2/day and 5-FU at 1750 mg/m2/day was administered as either a constant rate or as a circadian infusion over 72 h. During constant rate infusions, 5-FU concentrations within individuals varied by 1.7-fold, but no uniform time of peak or trough concentration was observed. Transformation of these data by setting the time of peak to 0 h and by expressing concentrations as the percentage of the 24-h mean value revealed a nonrandom distribution of the time from peak to trough with a median time of 12 h (P = 0.027). These transformed data were also successfully fit to a circadian cosinor function (P < 0.001). During multiple constant rate 5-FU infusions, the intrapatient variability was high; the times of peak 5-FU concentration occurred at the same approximate sampling time 43% of the time, and troughs coincided 17% of the time. No difference in clinical toxicity was observed when matched constant rate and circadian infusions of 5-FU were compared. High inter- and intrapatient variability exists in 5-FU plasma concentrations in adult cancer patients during constant rate infusions with no evidence of a consistent circadian rhythm in untransformed data.
authors.affiliation: Developmental Therapeutics Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland 20889, USA. ctakim@helix.nih.gov
authors.forename: C H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: L K
authors.initials: LK
authors.lastname: Yee
authors.forename: D J
authors.initials: DJ
authors.lastname: Venzon
authors.forename: B
authors.initials: B
authors.lastname: Schuler
authors.forename: F
authors.initials: F
authors.lastname: Grollman
authors.forename: C
authors.initials: C
authors.lastname: Chabuk
authors.forename: J M
authors.initials: JM
authors.lastname: Hamilton
authors.forename: A P
authors.initials: AP
authors.lastname: Chen
authors.forename: C J
authors.initials: CJ
authors.lastname: Allegra
authors.forename: J L
authors.initials: JL
authors.lastname: Grem
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019454:Chronotherapy; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy; D004067:Digestive System Neoplasms / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy; D012004:Rectal Neoplasms / Q000097:blood / Q000188:drug therapy; D015203:Reproducibility of Results; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil