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Busulfan disposition in children
L B Grochow1, W Krivit, C B Whitley
1Division of Pharmacology and Experimental Therapeutics, Johns Hopkins Oncology Center, Baltimore, MD 21205.
Insights
Pediatric busulfan pharmacokinetics differ significantly from adults, with lower concentrations and higher clearance rates. This suggests a need for tailored dosing strategies in children undergoing bone marrow transplantation.
Area of Science:
- Pharmacology
- Pediatric Oncology
- Pharmacokinetics
Background:
- Busulfan is used in pediatric myeloablative therapy for bone marrow transplantation.
- Children exhibit low severe toxicity and engraftment failure rates with oral busulfan.
- Understanding pediatric busulfan disposition is crucial for optimizing treatment.
Purpose of the Study:
- To evaluate the pharmacokinetic disposition of oral busulfan in pediatric patients.
- To compare busulfan pharmacokinetics in children with those in adults.
- To inform potential dose adjustments for pediatric busulfan therapy.
Main Methods:
- Oral busulfan doses of 1 or 2 mg/kg were administered to children (2 months to 3.6 years).
- Gas chromatographic assay was used to measure busulfan concentrations.
- Pharmacokinetic parameters including peak concentration, half-life, AUC, volume of distribution, and clearance were calculated.
Main Results:
- Pediatric peak busulfan concentrations (1.4–5.2 μmol/L) were lower than in adults.
- Elimination half-life was slightly faster in children (92 min) compared to adults (140 min).
- Area under the curve was substantially lower in children, with higher volume of distribution and twice the clearance rate normalized to surface area.
Conclusions:
- Busulfan disposition in children differs markedly from adults, characterized by lower drug exposure and higher clearance.
- These pharmacokinetic differences may stem from altered bioavailability or volume of distribution.
- Separate phase I dose escalation studies with pharmacokinetic assessments are necessary for pediatric busulfan therapy.
Abstract:
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.