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Pharmacokinetics of high-dose busulfan in children
G Vassal1, A Gouyette, O Hartmann
1Clinical Pharmacology Unit (URA 158 CNRS, U 140 INSERM), Institut Gustave-Roussy, Villejuif, France.
Insights
High-dose oral busulfan in pediatric chemotherapy demonstrates predictable pharmacokinetics with consistent levels and significant central nervous system penetration. These findings support its use in bone marrow transplantation protocols.
Area of Science:
- Pharmacology
- Pediatric Oncology
- Pharmacokinetics
Background:
- High-dose busulfan is a key component in conditioning regimens prior to autologous bone marrow transplantation.
- Understanding busulfan pharmacokinetics in children is crucial for optimizing dosing and minimizing toxicity.
Purpose of the Study:
- To characterize the pharmacokinetics of high-dose oral busulfan in pediatric patients undergoing combined chemotherapy.
- To assess busulfan absorption, distribution, elimination, and central nervous system penetration.
Main Methods:
- Studied 12 children (mean age 7 years) receiving oral busulfan (1 mg/kg every 6 h for 4 days).
- Measured busulfan levels in plasma and cerebrospinal fluid (CSF) using gas chromatography-mass fragmentography.
- Analyzed pharmacokinetic parameters including maximal concentration, half-life, clearance, and distribution volume.
Main Results:
- Busulfan followed one-compartment model kinetics with zero-order absorption.
- Mean maximal concentration was 803 ng/ml, with a mean elimination half-life of 2.33 h.
- Mean CSF-to-plasma ratio was 0.95, indicating significant CNS penetration.
Conclusions:
- High-dose oral busulfan exhibits predictable pharmacokinetics in children.
- Consistent trough levels and significant CSF penetration were observed.
- Pharmacokinetic parameters remained stable throughout the 4-day treatment course.
Abstract:
The pharmacokinetics of high-dose busulfan given orally at 1 mg/kg every 6 h over 4 days (total dose, 16 mg/kg) in combined chemotherapy followed by autologous bone marrow transplantation was studied in 12 children with a mean age of 7 years (range, 4-14 years). Busulfan levels in biological fluids were measured by a gas chromatographic assay with mass fragmentographic detection, using a deuterated analogue as the internal standard. In a high-dose regimen, busulfan followed one-compartment model kinetics with zero-order absorption. A mean maximal concentration of 803 +/- 228 ng/ml was achieved at 92-255 min after dosing. The mean elimination half-life was 2.33 h, and the mean total clearance was 119 +/- 54 ml/min per m2, with an apparent distribution volume of 27.10 +/- 11.50 l/m2. A mean trough level of 370 ng/ml was found throughout the 4 days of the chemotherapy course. There were no significant variations in pharmacokinetic parameters measured after the first and last doses. Busulfan was monitored in the CSF of nine children at 3.25-7 h after the last dose and was detected in all patients, with a mean CSF-to-plasma concentration ratio of 0.95 (range, 0.5-1.4).