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


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.


CONCLUSIONS
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.
Foran
J M
JM
Imperial Cancer Research Fund Medical Oncology Unit, St Bartholomew's Hospital, London, United Kingdom. foran@icrf.icnet.uk
Oscier
D
D
Orchard
J
J
Johnson
S A
SA
Tighe
M
M
Cullen
M H
MH
de Takats
P G
PG
Kraus
C
C
Klein
M
M
Lister
T A
TA
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood* / Q000188:drug therapy; D008228:Lymphoma, Non-Hodgkin / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D001084:Vidarabine Phosphate / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D000964:Antimetabolites, Antineoplastic; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate