Busulfan disposition in children.
Children receive busulfan orally as part of myeloablative therapy before bone marrow transplantation for malignant and nonmalignant conditions. Children have been reported to have a low incidence of severe toxicity and significant rates of failure to achieve full engraftment. We evaluated the disposition of busulfan in children between 2 months and 3.6 years of age with lysosomal storage diseases, leukemia, and immunodeficiency disorders receiving oral doses of 1 or 2 mg/kg using a gas chromatographic assay. Peak concentrations were lower than those previously reported for adults, ranging from 1.4 to 5.2 mumol/L. The harmonic mean of the elimination half-life was 92 minutes, which is only slightly faster than that for adults (140 minutes). However, the area under the curve ranged from 400 to 1,000 (715 +/- 240) mumol.min/L, substantially lower than in adults receiving 1 mg/kg (range, 710 to 5,100 mumol.min/L; mean +/- SD, 2,180 +/- 1,200). The apparent volume of distribution (assuming complete bioavailability) ranged from 0.28 to 3.53 L/kg (1.42 +/- 0.86), which is more than twice that reported for adults (0.60 +/- 0.42). Busulfan clearance rate normalized to surface area is twice as high in children (200 +/- 100 mL/min/m2) as it is in adults (95 +/- 54 mL/min/m2). Alterations in bioavailability (absorption or first pass elimination) or in actual volume of distribution may account for these differences in drug disposition. The observed differences suggest the need for separate phase I dose escalation studies in children with accompanying pharmacokinetic assessment.
Grochow
L B
LB
Division of Pharmacology and Experimental Therapeutics, Johns Hopkins Oncology Center, Baltimore, MD 21205.
Krivit
W
W
Whitley
C B
CB
Blazar
B
B
D000284:Administration, Oral; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000187:drug effects; D006086:Graft vs Host Disease / Q000517:prevention & control; D006801:Humans; D007223:Infant
D002066:Busulfan