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 the pharmacokinetics of this drug in 25 pediatric patients with acute leukemia treated with cladribine as a single agent, 8.9 mg/m2/24 h, for 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 determined by a radioimmunoassay with a limit of detection of 1 nM. An open two-compartment model was fit to the plasma concentration data. The mean (SD) clearance was 39.4 (12.4) liters/h/m2 and ranged from 14.4-55.4 liters/h/m2. When clearance was normalized to body weight (liters/h/kg) it was negatively correlated with age, with older patients having slower clearances per unit of body weight. However, when clearance was normalized to body surface area, no significant correlation with age was observed. The mean (SD) steady-state plasma concentration (predicted 120-h concentration) was 37.7 (17.3) nM and ranged from 23.2-84.5 nM. The terminal phase half-life in 22 patients ranged from 14.3-25.8 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) liters/m2. None of these parameters was significantly different between patients in relapse and patients with newly diagnosed disease. Renal clearance was determined in 7 patients and ranged from 34.6-643.6 ml/min/m2, with a mean (SD) of 317.9 (208.7) ml/min/m2. Renal clearance 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 fluid concentration was 6.1 (3.97) nM, a mean of 18.2% of the steady-state plasma concentration. The CSF:plasma concentration ratio was significantly 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 comprehensive description of the pharmacokinetics of this drug in children and provide data which suggest that cladribine may be useful in the treatment of patients with meningeal leukemia or malignancies of the central nervous system.
Kearns
C M
CM
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Blakley
R L
RL
Santana
V M
VM
Crom
W R
WR
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D001663:Bilirubin / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D017338:Cladribine / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003404:Creatinine / Q000097:blood; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000378:metabolism*; D011237:Predictive Value of Tests
D017338:Cladribine; D003404:Creatinine; D001663:Bilirubin