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.
ASJC Scopus subject areas
- Cancer Research