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  • Title: Phase I trial and pharmacokinetic evaluation of fazarabine in children.
    Author: Heideman RL, Gillespie A, Ford H, Reaman GH, Balis FM, Tan C, Sato J, Ettinger LJ, Packer RJ, Poplack DG.
    Journal: Cancer Res; 1989 Sep 15; 49(18):5213-6. PubMed ID: 2475244.
    Abstract:
    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).
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