title: Busulfan disposition below the age of three: alteration in children with lysosomal storage disease.
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.
authors.affiliation: Clinical Pharmacology Laboratory (CNRS URA147, INSERM U140), Villejuif, France.
authors.forename: G
authors.initials: G
authors.lastname: Vassal
authors.forename: A
authors.initials: A
authors.lastname: Fischer
authors.forename: D
authors.initials: D
authors.lastname: Challine
authors.forename: I
authors.initials: I
authors.lastname: Boland
authors.forename: F
authors.initials: F
authors.lastname: Ledheist
authors.forename: S
authors.initials: S
authors.lastname: Lemerle
authors.forename: E
authors.initials: E
authors.lastname: Vilmer
authors.forename: C
authors.initials: C
authors.lastname: Rahimy
authors.forename: G
authors.initials: G
authors.lastname: Souillet
authors.forename: E
authors.initials: E
authors.lastname: Gluckman
mesh_terms: D000367:Age Factors; D001682:Biological Availability; D002066:Busulfan / Q000493:pharmacokinetics*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D016464:Lysosomal Storage Diseases / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate
chemical_list: D002066:Busulfan