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Foran, J.M. et al.

Foran, Oscier, Orchard, Johnson, Tighe, Cullen, de Takats, Kraus, Klein, Lister,

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

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-arabinofuranosyladenine (2F-ara-A) concentration (its main metabolite); area under the curve 0 to 24 hours (AUC(0-24h)) and maximum concentration (Cmax) 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 Cmax and AUC(0-24h) of 2F-ara-A and achieved an AUC(0-24h) similar to intravenous administration, although at a lower Cm. 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 Cmax 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.[1]

References

Pharmacokinetic study of single doses of oral fludarabine phosphate in patients with "low-grade" non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia. Foran, J.M., Oscier, D., Orchard, J., Johnson, S.A., Tighe, M., Cullen, M.H., de Takats, P.G., Kraus, C., Klein, M., Lister, T.A. J. Clin. Oncol. (1999) [Pubmed]

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