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Pharmacokinetic Study of Single Doses of Oral Fludarabine Phosphate in Patients With "Low-Grade" Non-Hodgkin's Lymphoma and B-Cell Chronic Lymphocytic Leukemia

From the Imperial Cancer Research Fund Medical Oncology Unit, St Bartholomew's Hospital, London, Department of Haematology, Royal Bournemouth Hospital, Bournemouth, Department of Haematology, Taunton and Somerset Hospital, Taunton, and Department of Oncology, Queen Elizabeth Hospital, Birmingham, United Kingdom; and Pharmacokinetics Therapeutics and Clinical Development Oncology, Schering AG, Berlin, Germany.

Address reprint requests to James M. Foran, MD, Imperial Cancer Research Fund Medical Oncology Unit, Department of Medical Oncology, 45 Little Britain, 2nd Floor, St Bartholomew's Hospital, London, EC1A 7BE United Kingdom; email foran{at}icrf.icnet.uk

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 on 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-arabinofuranosyl-adenine (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. Bioavailability (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.

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