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Busulfan disposition below the age of three: alteration in children with lysosomal storage disease
G Vassal1, A Fischer, D Challine
1Clinical Pharmacology Laboratory (CNRS URA147, INSERM U140), Villejuif, France.
Insights
Busulfan clearance is higher in young children than adults, varying significantly with disease. Dose adjustments and drug monitoring are crucial for optimal busulfan dosing in pediatric patients.
Area of Science:
- Pharmacology
- Pediatric Oncology
- Pharmacokinetics
Background:
- Busulfan (Bu) dosing in children requires age-specific adjustments due to variable disposition.
- Optimal busulfan dosage for bone marrow (BM) ablation in young children is not well-defined.
- Busulfan pharmacokinetics differ between pediatric age groups and adults.
Purpose of the Study:
- To evaluate busulfan pharmacokinetics in young children receiving oral busulfan.
- To determine if busulfan disposition varies in children with specific diseases, such as lysosomal storage diseases (LSDs).
- To inform optimal busulfan dosing strategies in pediatric patients.
Main Methods:
- Plasma pharmacokinetics of busulfan were analyzed in 33 children (2 months to 2.75 years) using gas chromatography-mass spectrometry.
- Oral busulfan doses ranged from 0.9 to 2.6 mg/kg.
- Busulfan clearance, volume of distribution, and elimination half-life were calculated.
Main Results:
- Busulfan clearance (mean 6.8 mL/min/kg) was higher in young children compared to older children and adults.
- Children with LSDs exhibited a prolonged elimination half-life (4.9 vs 2.4 hours) and larger volume of distribution (3.4 vs 1.2 L/kg) than other children.
- Busulfan pharmacokinetics were linear over the studied dose range, but dose accounted for only 46% of exposure variation.
Conclusions:
- Busulfan disposition is highly variable in young children, necessitating dose adjustments and therapeutic drug monitoring.
- Children with LSDs may require higher busulfan doses for effective BM ablation.
- Further research is needed to define target plasma busulfan levels for BM displacement, particularly in LSDs.
Abstract:
Busulfan disposition is age-dependent with a higher clearance and a larger volume of distribution in children than in adults. The optimal dosage of busulfan needed to achieve bone marrow (BM) displacement in young children with malignant or nonmalignant disease remains to be defined. Using a gas chromatography-mass spectrometry assay, we evaluated plasma pharmacokinetics of busulfan in 33 children (median age, 9 months; range, 2 months to 2.75 years) with immune deficiencies, lysosomal storage diseases, acute leukemias, and malignant lymphohistiocytosis after an oral dose ranging from 0.9 to 2.6 mg/kg. The busulfan clearance (assuming a bioavailability of 1) ranged from 2.1 to 13.4 mL/min/kg with a mean of 6.8 mL/min/kg, which is higher than that reported in older children (4.5 mL/min/kg) and adults (2.9 mL/min/kg). Six children with lysosomal storage disease (5 with Hurler's disease, 1 with San Filippo's disease) had a prolonged elimination half-life (4.9 v 2.4 hours), a larger volume of distribution (3.4 v 1.2 L/kg) and a faster clearance (8.7 v 6.3 mL/min/kg) than the other 27 children. This suggests that a higher dose of busulfan will be required to achieve BM displacement in children with lysosomal storage disease. Over the dose range of 0.9 to 2.6 mg/kg, busulfan pharmacokinetics were linear. However, only 46% of the interpatient variation in systemic exposure could be ascribed to the dose. Given the wide interpatient variability in busulfan disposition, dose adjustment and drug monitoring will be needed to achieve the optimal dosage of busulfan in young children. The plasma busulfan levels required to achieve BM displacement need to be defined, especially in lysosomal storage diseases.