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Is 600 mg/m2 the appropriate dosage of busulfan in children undergoing bone marrow transplantation?
G Vassal1, A Deroussent, D Challine
1Clinical Pharmacology Laboratory (CNRS URA147, INSERM U140), Villejuif, France.
Insights
High-dose busulfan pharmacokinetics in children undergoing bone marrow transplantation (BMT) are now better understood. A new dosage based on body surface area (BSA) significantly increases systemic exposure in children, reducing age-dependent differences.
Area of Science:
- Pharmacology
- Pediatric Oncology
- Hematology
Background:
- Busulfan pharmacokinetics in bone marrow transplantation (BMT) are age-dependent.
- Children typically have lower systemic exposure to high-dose busulfan compared to adults.
- Previous dosing strategies may lead to suboptimal therapeutic levels in pediatric patients.
Purpose of the Study:
- To evaluate the pharmacokinetics of a new high-dose busulfan regimen in children undergoing BMT.
- To determine if a body surface area (BSA)-based dosage improves systemic exposure in pediatric BMT.
- To compare busulfan exposure in children on the new regimen with historical adult data.
Main Methods:
- Plasma pharmacokinetics of busulfan were measured in 27 children (mean age 5.4 years).
- Children received a new dosage of 600 mg/m2 over 4 days.
- A gas chromatography-mass spectrometry assay was utilized for busulfan quantification.
Main Results:
- The new BSA-based dosage (600 mg/m2) significantly increased systemic exposure in children compared to the standard 16 mg/kg dose.
- Systemic exposure in children on the new regimen was comparable to that of adults receiving 16 mg/kg.
- Wide interindividual variation in systemic exposure persisted despite BSA normalization.
Conclusions:
- A BSA-based dosage of busulfan (600 mg/m2) improves systemic exposure in pediatric BMT patients.
- While BSA normalization reduces age-related pharmacokinetic differences, individual variability remains.
- Optimal busulfan dosing in children may require further individualization through dose adjustment and plasma level monitoring.
Abstract:
Recent studies have reported that the pharmacokinetics of high-dose busulfan in bone marrow transplantation (BMT) are age-dependent: with the usual dosage of 16 mg/kg over 4 days, systemic exposure is two to four times lower in children than in adults. Data suggested that the dose of busulfan should rather be calculated on the basis of the body surface area (BSA). We measured plasma pharmacokinetics of busulfan in 27 children (mean age, 5.4 years) who were administered a new dosage of 600 mg/m2 over 4 days, ie, 17.8 to 29.2 mg/kg (mean, 24.8 mg/kg), using a gas chromatography-mass spectrometry assay. Our results demonstrate that, with this new dosage, systemic exposure is significantly increased in children compared with that achieved with the usual dosage of 16 mg/kg (6,404 +/- 2,378 v 3,918 +/- 1,170 ng.h/mL; P = .003). Moreover, there is no longer a significant difference in systemic exposure between children treated with this new dosage and adults given a dose of 16 mg/kg of busulfan. However, despite the use of a dosage normalized to the BSA, there is still a wide interindividual variation in systemic exposure, ranging from 3,566 to 13,129 ng.h/mL, which may account for the high incidence of venoocclusive disease (VOD) of the liver that we have already reported. The optimal dosage and schedule of busulfan in children requires a more individual approach that could be based on dose adjustment and plasma level monitoring.