Phase I trial and pharmacokinetic evaluation of fazarabine in children

• Published in: Cancer research (Chicago, Ill.) Vol. 49; no. 18; pp. 5213 - 5216
• Main Authors: HEIDEMAN, R. L, GILLESPIE, A, FORD, H, REAMAN, G. H, BALIS, F. M, TAN, C, SATO, J, ETTINGER, L. J, PACKER, R. J, POPLACK, D. G
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-09-1989
• Subjects: Antimetabolites, Antineoplastic - adverse effects; Antineoplastic agents; Azacitidine - adverse effects; Azacitidine - pharmacokinetics; Azacitidine - therapeutic use; Biological and medical sciences; Child; Drug Evaluation; Female; General aspects; Humans; Infusions, Intravenous; Male; Medical sciences; Metabolic Clearance Rate; Neoplasms - drug therapy; Pharmacology. Drug treatments; Human; Antineoplastic agent; Phase I trial; Chemotherapy; Treatment; Child
• ISSN: 0008-5472; 1538-7445

A phase I trial of fazarabine (1-beta-D-arabinofuranosyl-5-azacytosine, NSC 281272) administered as a 24-h continuous infusion was performed in 16 children with refractory malignancies. Dose-limiting toxicity consisting of reversible granulocytopenia and thrombocytopenia was observed in 4 of 4 solid tumor patients treated at the starting dose of 20 mg/m2/h. Subsequent patients were treated at a dose of 15 mg/m2/h which was determined to be the maximum tolerated dose. Moderate nausea and vomiting were the only other toxicities observed. Plasma steady-state concentrations of fazarabine were attained by 2-4 h in all patients and were 1.8 and 2.5 microM at the 15- and 20-mg/m2/h doses, respectively. The total body clearance of fazarabine was 571 and 550 ml/min/m2 at the 15- and 20-mg/m2/h doses, respectively. In three of four patients evaluated, fazarabine was detectable in the cerebrospinal fluid (CSF). Steady-state CSF concentrations ranged from 0.29 to 0.74 microM in these three individuals and the steady-state CSF:plasma ratios ranged from 0.22-0.25. Both the plasma and CSF steady-state concentrations were within the 0.1 to 1 microM range reported to be cytotoxic in vitro against the Molt-4 human T-lymphoblastic leukemia cell line. Based on the above, the optimal dose for phase II trials of fazarabine administered as a 24-h infusion is 15 mg/m2/h (360 mg/m2/day).