Pharmacology of fludarabine phosphate after a phase I/II trial by a loading bolus and continuous infusion in pediatric patients.
Fludarabine phosphate is a nucleotide analogue of adenine arabinoside with antitumor activity in murine and human lymphoid malignancies; it has occasional, unpredictable neurotoxicity after high dose bolus injections in adults. To avoid this toxicity, we studied a loading dose plus 5-day continuous infusion in 47 evaluable pediatric patients. Dose limiting myelosuppression was seen in children with solid tumors after a loading dose of 8 mg/m2 followed by 23.5 mg/m2/day for 5 days. In children with leukemia, no dose limiting toxicity was seen at dose level 6, consisting of a loading dose of 10 mg/m2 and an infusion of 30.5 mg/m2/day for 5 days. One complete and 3 partial remissions were seen in 26 evaluable children with acute lymphoblastic leukemia. 9-beta-D-arabinofuranosyl-2-fluoroadenine plasma concentrations and the area under the moment curve increased linearly with dose. The terminal half-life was similar, while the total body clearance was shorter than that reported for adults receiving bolus or continuous doses. Lymphoblasts isolated from 2 patients during fludarabine phosphate (9-beta-D-arabinofuranosyl-2-fluoroadenine) treatment increased their ability to convert 1-beta-D-arabinofuranosylcytosine to 1-beta-D-arabinofuranosylcytosine 5'-triphosphate by more than 10-fold. The antileukemic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-phosphate and its ability to alter the metabolism of 1-beta-D-arabinofuranosylcytosine indicate that timed combinations of these 2 agents should be tested.
Childrens Hospital Los Angeles, Division of Hematology/Oncology, University of Southern California 90027.
V I
VI
Avramis
J
J
Champagne
J
J
Sato
M
M
Krailo
L J
LJ
Ettinger
D G
DG
Poplack
J
J
Finkelstein
G
G
Reaman
G D
GD
Hammond
J S
JS
Holcenberg
D000964:Antimetabolites, Antineoplastic; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D002675:Child, Preschool; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D001084:Vidarabine Phosphate / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D001084:Vidarabine Phosphate; D001085:Arabinofuranosylcytosine Triphosphate; C042382:fludarabine phosphate