Journal of Clinical Oncology, Vol 11, 751-761, Copyright © 1993 by American Society of Clinical Oncology
Phase I and plasma pharmacokinetic study of infusional fluorouracil combined with recombinant interferon alfa-2b in patients with advanced cancer
LL Danhauser, JH Freimann Jr, TL Gilchrist, JU Gutterman, CY Hunter, AC Yeomans and AB Markowitz
Department of Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
PURPOSE: Enhanced fluorouracil (FUra) cytotoxicity caused by recombinant
interferon alfa-2b (rIFN-a) has been reported, but the mechanism, optimal
dose, and schedule remain unknown. Therefore, a phase I and pharmacokinetic
study of FUra with escalating doses of rIFN- a was initiated. PATIENTS AND
METHODS: FUra (750 mg/m2/d) was given by continuous intravenous (IV)
infusion for 5 days. rIFN-a (0.1 to 15 x 10(6) U/m2/d) was given
subcutaneously (SC) daily for 5 days concurrent with FUra. Courses were
repeated every 14 to 21 days. Forty-four patients were enrolled; 39
received at least two courses. During the first course of therapy, FUra
levels before and after administration of rIFN-a were quantitated in 26
patients by high-pressure liquid chromatography. RESULTS: The
maximum-tolerated dose of rIFN-a was 10 x 10(6) U/m2/d. Stomatitis was
dose-limiting. Three partial and five minor responses occurred.
Interpatient pharmacokinetics showed that rIFN-a did not alter steady-state
plasma concentration (Css; range, 0.77 +/- 0.35 mumol/L to 1.85 +/- 0.48
mumol/L), elimination half-life (t1/2; mean, 9.7 +/- 4.3 minutes), area
under the concentration-versus- time curve (AUC; range, 93 to 224 mumol/L x
hours), total-body clearance (CI; range, 1,172 to 3,236 mL/min), or volume
of distribution (range, 11.9 to 49.2 L) of FUra. Intrapatient data
evaluation revealed a dose-independent effect of rIFN-a. The mean FUra Css
after rIFN-a administration (1.31 mumol/L) was greater than that before
rIFN-a administration (1.02 mumol/L, P < .0001). FUra Cl after rIFN-a
administration was reduced by 20% to 35% compared with use of FUra alone (P
< .0001). Patients with a greater than 20% decrease in FUra Cl had a
fourfold greater incidence of diarrhea. CONCLUSION: rIFN-a reduces FUra Cl
and, consequently, increases FUra-associated toxicity. Phase II studies of
FUra and rIFN-a seem to be warranted.
