Pharmacokinetics and pharmacodynamic effects of 5-fluorouracil given as a one-hour intravenous infusion.
OBJECTIVE
Clinical toxicity associated with 5-fluorouracil (5-FU) is related to the area under the plasma concentration-time curve (AUC). Recently, short-term infusions of 5-FU given over 30 or 60 min have been substituted for conventional "bolus" 5-FU given over 3-5 min in randomized clinical trials, but there are only limited pharmacokinetic data for these altered infusion durations. We therefore wished to determine the pharmacokinetics and toxicity associated with 5-FU given as a 1-h intravenous (i.v.) infusion.


METHODS
A group of 22 adults with advanced gastrointestinal tract cancers and no prior systemic chemotherapy for advanced disease received interferon alpha-2a (5 MU/m2 s.c., days 1-7), leucovorin (500 mg/m2 i.v. over 30 min, days 2-6) and 5-FU (370 mg/m2 i.v. over 1 h, days 2-6). The doses of 5-FU and interferon-alpha were adjusted according to individual tolerance. The pharmacokinetics and clinical toxicity were retrospectively compared with patients receiving the same regimen under the same treatment guidelines except that 5-FU was given over 5 min.


RESULTS
The regimen was well tolerated, and 41% of the patients tolerated 5-FU dose escalations to 425-560 mg/m2 per day. Grade 3 or worse diarrhea and fatigue ultimately occurred in 14% of the patients each. Granulocytopenia, mucositis, and diarrhea appeared to be appreciably milder in the present trial compared with our prior phase II experience in colorectal cancer. The peak 5-FU plasma levels and AUC with 370 mg/m2 5-FU given over 1 h were 7.3-fold and 2.4-fold lower than previously measured in 31 patients who received 5-FU over 5 min.


CONCLUSIONS
Increasing the length of 5-FU infusion to 1 h seemed to substantially reduce the clinical toxicity with this modulated 5-FU regimen, likely due to markedly lower peak 5-FU plasma levels and AUC. Changes in the duration of a short infusion of 5-FU clearly affects the clinical toxicity, but raises the concern of a potentially adverse impact on its antitumor activity. These results suggest the importance of including precise guidelines concerning the time over which 5-FU is given in clinical trials. Having a specified duration of 5-FU infusion is also important if 5-FU dose escalation is considered.
Grem
J L
JL
National Cancer Institute-Medicine Branch, National Naval Medical Center, Bethesda, MD 20889, USA. jgrem@helix.nih.gov
Quinn
M
M
Ismail
A S
AS
Takimoto
C H
CH
Lush
R
R
Liewehr
D J
DJ
Steinberg
S M
SM
Balis
F M
FM
Chen
A P
AP
Monahan
B P
BP
Harold
N
N
Corse
W
W
Pang
J
J
Murphy
R F
RF
Allegra
C J
CJ
Hamilton
J M
JM
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D019540:Area Under Curve; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil