PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF FLUDARABINE AND CYTOSINE-ARABINOSIDE ADMINISTERED AS LOADING BOLUSES FOLLOWED BY CONTINUOUS INFUSIONS AFTER A PHASE I II STUDY IN PEDIATRIC-PATIENTS WITH RELAPSEDLEUKEMIAS/
Vi. Avramis et al., PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF FLUDARABINE AND CYTOSINE-ARABINOSIDE ADMINISTERED AS LOADING BOLUSES FOLLOWED BY CONTINUOUS INFUSIONS AFTER A PHASE I II STUDY IN PEDIATRIC-PATIENTS WITH RELAPSEDLEUKEMIAS/, Clinical cancer research, 4(1), 1998, pp. 45-52
The sequential administration of fludarabine followed by cytosine arab
inoside (ara-C) has demonstrated significant synergistic effects again
st the CEM human leukemic cell line. This in vitro synergism was inves
tigated in a Phase I trial in pediatric patients with relapsed acute l
eukemia, The optimum concentrations of 9-beta-D-arabinofuranosyl 2-flu
oroadenine and ara-C necessary Xo achieve significant drug synergism f
rom in vitro studies were between 10 and 20 mu M. Fludarabine was infu
sed at a dose to attain a target plasma concentration of 10 mu M for 4
8 h, followed by a continuous infusion of escalated ara-C doses to mai
ntain plasma ara-C concentrations of 10, 12.5, 15, or 17.5 mu M for 72
h, Thirteen patients with acute lymphocytic leukemia and 18 with acut
e myelocytic leukemia were entered into the study, 30 of whom were cli
nically evaluable for toxicity, Pharmacokinetic and pharmacodynamic st
udies were performed on specimens from 20 patients, The optimal 9-beta
-D-arabinofuranosyl 3-fluoroadenine and ara-C concentrations in plasma
were easily achieved after continuous infusion regimens of both drugs
, Cellular ara-CTP is augmented 5-8-fold in leukemic cells from patien
ts receiving fludarabine phosphate treatment followed by ara-C, The ma
ximum tolerated plasma concentrations for this combination regimen was
10 mu M fludarabine for 48 h followed by 72 h of 15 mu M ara-C, which
were achieved at dose level 3, A significant number of responses were
also seen, Nine of 18 evaluable patients (50%) with acute myelocytic
leukemia achieved complete or partial responses, and 3 of 9 evaluable
patients with acute lymphocytic leukemia achieved complete or partial
responses, Fludarabine and ara-C successfully eradicated bone marrow d
isease in 16 of 27 patients (59%), 23 patients of which had been treat
ed previously with high-dose ara-C. These results verified the synergi
stic effect fludarabine exhibited in augmenting ara-CTP concentrations
in patients' leukemic blasts, thus improving the clinical response in
relapsed pediatric leukemias.