Pharmacokinetic study of single doses of oral fludarabine phosphate in patients with 'low-grade' non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia

James M. Foran, David Oscier, Jennifer Orchard, Stephen A. Johnson, Mary Tighe, Michael H. Cullen, Philippa G. De Takats, Christian Kraus, Marcus Klein, T. Andrew Lister

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Purpose: Fludarabine phosphate (F-AMP), a purine analog, requires daily intravenous administration. A pharmacokinetic study of an oral formulation (10 mg immediate-release tablet) was undertaken in patients with 'low-grade' non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia. Patients and Methods: Oral F-AMP was incorporated into the 'conventional' treatment schedule. Single oral trial doses of 50, 70, and 90 mg of F-AMP were given an the first day of three cycles of treatment; a comparative 50-mg intravenous trial dose was given on the first day of the fourth cycle. Intravenous F-AMP (25 mg/m2) was given on days 2 to 5 at 4-week intervals. Pharmacokinetic samples taken after each trial dose were analyzed for plasma 2-fluoro- arabinofuranosyladenine (2F-ara-A) concentration (its main metabolite); area under the curve 0 to 24 hours (AUC(0-24h)) and maximum concentration (C(max)) were calculated. Eighteen patients received all three oral trial doses, and bioavailability was determined in 15 patients who completed four courses of therapy. Results: Oral administration of F-AMP resulted in a dose-dependent increase in C(max) and AUC(0-24h) of 2F-ara-A and achieved an AUC(0-24h) similar to intravenous administration, although at a lower C(max). The linear increase in mean AUC(0-24h) by factors of 1.36 ± 0.22 (mean ± SD) and 1.72 ± 0.31 corresponded well with the increase in oral dose from 50 to 70 mg (factor of 1.4) and 90 mg (factor of 1.8), respectively. Bioavailabillty (approximately 55%, with low intraindividual variation) and time to C(max) were dose independent. Conclusion: Oral doses of F-AMP can achieve an AUC(0- 24h) of 2F-ara-A similar to intravenous administration, with dose-independent bioavailability. The tablet will greatly enhance the use of F-AMP in a palliative setting.

Original languageEnglish (US)
Pages (from-to)1574-1579
Number of pages6
JournalJournal of Clinical Oncology
Volume17
Issue number5
DOIs
StatePublished - May 1999

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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