Pharmacokinetics of nelarabine and 9-beta-D-arabinofuranosyl guanine in pediatric and adult patients during a phase I study of nelarabine for the treatment of refractory hematologic malignancies

Purpose: To characterise the pharmacokinetics of nelarabine (506U78), the w ater-soluble prodrug of 9-beta-D arabinofuranosyl guanine (ara-G), and ara- G in pediatric and adult patients with refractory hematologic malignancies. Ara-G is phosphorylated within leukemic cells to form ara-G triphosphate ( ara-GTP), which acts to terminate DNA chain elongation, resulting in cell d eath. Patients and Methods: The pharmacokinetics of nelarabine and/or ara-G were evaluated in 71 patients (25 pediatric and 46 adult patients) on the first day of therapy. Blood was collected at specified times for the determinatio n of plasma nelarabine and ara-G concentrations. Results: There were no statistically significant differences in the pharmac okinetics of nelarabine between any of the groups of patients. The harmonic mean half-life (t1/2) of nelarabine in pediatric and adult patients was 14 .1 minutes and 16.5 minutes, respectively. The maximum concentrations (C-ma x) of ara-G occurred at or near the end of the nelarabine infusion. The C-m ax of ara-G ranged from 11.6 mu mol/L to 308.7 mu mol/L at nelarabine doses of 5 to 75 mg/kg and was linearly related to the nelarabine dose. No stati stically significant differences were noted for the pharmacokinetic paramet er estimates of ara-G between adult male and female patients. In children v ersus adults, the dose-normalized C-max time of the C-max and the steady-st ate volume of distribution of ara-G were similar. However, the clearance of ara-G was higher in pediatric patients (0.312 L.h(-1).kg(-1)) as compared with adult patients (0.213 L.h(-1).kg(-1)) (P < .001), The t1/2 of ara-G wa s shorter in pediatric patients as compared with adult patients (2.1 hours v 3.0 hours; P < .01). Conclusion: Nelarabine is an effective prodrug of ara-G, allowing systemic concentrations of ara-G that result in clinical activity. J Clin Oncol 18:9 95-1003. (C) 2000 by American Society of Clinical Oncology.