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/

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.