This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Baker, S. D. Articles by Rowinsky, E. K. Search for Related Content PubMed PubMed Citation Articles by Baker, S. D. Articles by Rowinsky, E. K. Social Bookmarking                            What's this?

Phase I and Pharmacologic Study of Oral Fluorouracil on a Chronic Daily Schedule in Combination With the Dihydropyrimidine Dehydrogenase Inactivator Eniluracil

From The Johns Hopkins Oncology Center, Baltimore, MD; University of Alabama, Birmingham, AL; and Glaxo Wellcome, Inc, Research Triangle Park, NC.

Address reprint requests to Sharyn D. Baker, PharmD, Division of Pharmacology and Experimental Therapeutics, The Johns Hopkins Cancer Research Building, 1650 Orleans St, Room 1M87, Baltimore, MD 21207; email sdbaker{at}jhmi.edu

PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and pharmacokinetics of oral fluorouracil (5-FU) administered twice daily in combination with oral eniluracil, an inactivator of dihydropyrimidine dehydrogenase, administered for 28 days every 35 days.

PATIENTS AND METHODS: Oral 5-FU 1.35 mg/m² twice daily was administered with oral eniluracil 10 mg daily for 14 to 28 days, followed by a 1-week rest period. Eniluracil was started 1 day before 5-FU. Patients then received escalated doses of oral 5-FU 1.35 to 1.8 mg/m² twice daily with an increased dose of eniluracil 10 mg twice daily for 28 days. A reduced dose of 5-FU 1.0 mg/m² with eniluracil 20 mg twice daily was evaluated.

RESULTS: Thirty-six patients with solid malignancies were enrolled onto the study. Diarrhea was the principal dose-limiting toxicity of oral 5-FU and eniluracil given on this chronic schedule. The recommended phase II dose is 5-FU 1.0 mg/m² twice daily with eniluracil 20 mg twice daily. Mean (SD) values for terminal half-life, apparent volume of distribution, and systemic clearance of 4.5 hours (0.83 hours), 19 L/m² (3.0 L/m²), and 51 mL/min/m² (13 mL/min/m²), respectively. An average of 77% of 5-FU was excreted unchanged in urine after 28 days of treatment. The mean (range) 5-FU C_SS,min values achieved at the 1.0 mg/m² dose level were 22 ng/mL (8 to 38 ng/mL).

CONCLUSION: Chronic oral administration of 5-FU with oral eniluracil is tolerable and produces 5-FU steady-state concentrations similar to those achieved with protracted intravenous administration of 5-FU on clinically relevant dose schedules. Eniluracil provides an attractive means of administering 5-FU on protracted schedules.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				Q. S.-C. Chu, L. A. Hammond, G. Schwartz, L. Ochoa, S.-Y. Rha, L. Denis, K. Molpus, B. Roedig, S. P. Letrent, B. Damle, et al. Phase I and Pharmacokinetic Study of the Oral Fluoropyrimidine S-1 on a Once-Daily-for-28-Day Schedule in Patients with Advanced Malignancies Clin. Cancer Res., August 1, 2004; 10(15): 4913 - 4921. [Abstract] [Full Text] [PDF]

				A. C. Wolff, R. C. Donehower, M. K. Carducci, M. A. Carducci, J. R. Brahmer, Y. Zabelina, M. O. Bradley, F. H. Anthony, C. S. Swindell, P. A. Witman, et al. Phase I Study of Docosahexaenoic Acid-Paclitaxel: a Taxane-Fatty Acid Conjugate with a Unique Pharmacology and Toxicity Profile Clin. Cancer Res., September 1, 2003; 9(10): 3589 - 3597. [Abstract] [Full Text] [PDF]

				D. Yip, C. Karapetis, A. H. Strickland, C. Steer, C. Holford, S. Knight, and P. Harper A dose-escalating study of oral eniluracil/5-fluorouracil plus oxaliplatin in patients with advanced gastrointestinal malignancies Ann. Onc., June 1, 2003; 14(6): 864 - 866. [Abstract] [Full Text] [PDF]

				S. D. Baker, J. Verweij, E. K. Rowinsky, R. C. Donehower, J. H. M. Schellens, L. B. Grochow, and A. Sparreboom Role of Body Surface Area in Dosing of Investigational Anticancer Agents in Adults, 1991-2001 J Natl Cancer Inst, December 18, 2002; 94(24): 1883 - 1888. [Abstract] [Full Text] [PDF]

				M. L. Rothenberg, J. K. Benedetti, J. S. Macdonald, T. E. Seay, M. A. Neubauer, C. S. George, M. S. Tanaka, J. K. Giguere, B. T. Pruitt, and J. L. Abbruzzese Phase II trial of 5-fluorouracil plus eniluracil in patients with advanced pancreatic cancer: a Southwest Oncology Group study Ann. Onc., October 1, 2002; 13(10): 1576 - 1582. [Abstract] [Full Text] [PDF]

				B. Keith, X.-D. Guo, S. Zentko, N. Harold, B. Schuler, M. Quinn, J. Shapiro, and J. L. Grem Impact of Two Weekly Schedules of Oral Eniluracil Given with Fluorouracil and Leucovorin on the Duration of Dihydropyrimidine Dehydrogenase Inhibition Clin. Cancer Res., May 1, 2002; 8(5): 1045 - 1050. [Abstract] [Full Text] [PDF]

				A. B. Benson III, E. Mitchell, N. Abramson, B. Klencke, P. Ritch, J. P. Burnham, C. McGuirt, T. Bonny, J. Levin, and J. Hohneker Oral eniluracil/5-fluorouracil in patients with inoperable hepatocellular carcinoma Ann. Onc., April 1, 2002; 13(4): 576 - 581. [Abstract] [Full Text] [PDF]

				R. L. Schilsky, J. Levin, W. H. West, A. Wong, B. Colwell, M. P. Thirlwell, R. H. Ansari, W. N. Bell, R. L. White, B. B. Yates, et al. Randomized, Open-Label, Phase III Study of a 28-Day Oral Regimen of Eniluracil Plus Fluorouracil Versus Intravenous Fluorouracil Plus Leucovorin as First-Line Therapy in Patients With Metastatic/Advanced Colorectal Cancer J. Clin. Oncol., March 15, 2002; 20(6): 1519 - 1526. [Abstract] [Full Text] [PDF]

				A. A. Adjei, J. M. Reid, R. B Diasio, J. A. Sloan, D. A. Smith, J. Rubin, H. C. Pitot, S. R. Alberts, R. M. Goldberg, L. J. Hanson, et al. Comparative Pharmacokinetic Study of Continuous Venous Infusion Fluorouracil and Oral Fluorouracil With Eniluracil in Patients With Advanced Solid Tumors J. Clin. Oncol., March 15, 2002; 20(6): 1683 - 1691. [Abstract] [Full Text] [PDF]

				R. B. Diasio An Evolving Role for Oral Fluoropyrimidine Drugs J. Clin. Oncol., February 15, 2002; 20(4): 894 - 896. [Full Text] [PDF]

				E. Rivera, L. Sutton, B. Colwell, M. Graham, D. Frye, M. Somerville, H. S. Conklin, C. McGuirt, J. Levin, and G. N. Hortobagyi Multicenter Phase II Study of a 28-Day Regimen of Orally Administered Eniluracil and Fluorouracil in the Treatment of Patients With Anthracycline- and Taxane-Resistant Advanced Breast Cancer J. Clin. Oncol., February 15, 2002; 20(4): 987 - 993. [Abstract] [Full Text] [PDF]

				J. L. Grem, N. Harold, J. Shapiro, D.-Q. Bi, M. G. Quinn, S. Zentko, B. Keith, J. M. Hamilton, B. P. Monahan, S. Donavan, et al. Phase I and Pharmacokinetic Trial of Weekly Oral Fluorouracil Given With Eniluracil and Low-Dose Leucovorin to Patients With Solid Tumors J. Clin. Oncol., December 1, 2000; 18(23): 3952 - 3963. [Abstract] [Full Text] [PDF]

				S. Mani, H. Hochster, T. Beck, E. M. Chevlen, M. A. O'Rourke, C. H. Weaver, W. N. Bell, R. White, C. McGuirt, J. Levin, et al. Multicenter Phase II Study to Evaluate a 28-Day Regimen of Oral Fluorouracil Plus Eniluracil in the Treatment of Patients With Previously Untreated Metastatic Colorectal Cancer J. Clin. Oncol., August 15, 2000; 18(15): 2894 - 2901. [Abstract] [Full Text] [PDF]