PHARMACOKINETICS OF CLADRIBINE (2-CHLORODEOXYADENOSINE) IN CHILDREN WITH ACUTE-LEUKEMIA

Cladribine is a synthetic purine nucleoside with demonstrated activity in hairy cell leukemia and acute myeloid leukemia. We have studied th e pharmacokinetics of this drug in 25 pediatric patients with acute le ukemia treated with cladribine as a single agent, 8.9 mg/m(2)/24 h, fo r 5 days by continuous i.v. infusion. Twelve patients were in relapse, and acute myeloid leukemia was newly diagnosed in 13 patients. Plasma , urine, and cerebrospinal fluid cladribine concentrations were determ ined by a radioimmunoassay with a limit of detection of 1 nM. An open two-compartment model was fit to the plasma concentration data. The me an (SD) clearance was 39.4 (12.4) liters/h/m(2) and ranged from 14.4-5 5.4 liters/h/ m(2). When clearance was normalized to body weight (lite rs/h/kg) it was negatively correlated with age, with older patients ha ving slower clearances per unit of body weight. However, when clearanc e was normalized to body surface area, no significant correlation with age was observed. The mean (SD) steady-state plasma concentration (pr edicted 120-h concentration) was 37.7 (17.3) nM and ranged from 23.2-8 4.5 nM. The terminal phase half-life in 22 patients ranged from 14.3-2 5.8 h, with a mean (SD) of 19.7 (3.4) h. The volume of distribution at steady state was highly variable, with a mean (SD) of 356.6 (225.2) l iters/m(2). None of these parameters was significantly different betwe en patients in relapse and patients with newly diagnosed disease. Rena l clearance was determined in 7 patients and ranged from 34.6-643.6 ml /min/m(2), with a mean (SD) of 317.9 (208.7) ml/min/m(2). Penal cleara nce as a percentage of total systemic clearance ranged from 11.0-85.1% , with a mean of 51.0%. In 11 patients, the mean (SD) cerebrospinal fl uid concentration was 6.1 (3.97) nM, a mean of 18.2% of the steady-sta te plasma concentration. The CSF:plasma concentration ratio was signif icantly higher on day 5 (22.7% in 7 patients) than on day 4 (7.6% in 3 patients; P = 0.03). Additional studies are needed to further define the metabolic fate of cladribine. In this paper we provide the first c omprehensive description of the pharmacokinetics of this drug in child ren and provide data which suggest that cladribine may be useful in th e treatment of patients with meningeal leukemia or malignancies of the central nervous system.