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Retrospective appraisal of busulfan dose adjustment in children
L L Dupuis1, M Najdova, E F Saunders
1Department of Pharmacy, The Hospital For Sick Children, Toronto, Ontario, Canada.
Insights
Adjusting busulfan dosage in pediatric bone marrow transplant patients is crucial. Dosing should be individualized based on age and weight, using a four-sample method for accurate area under the curve (AUC) calculation.
Area of Science:
- Pediatric Hematology
- Pharmacokinetics
- Bone Marrow Transplantation
Background:
- Busulfan is a key chemotherapeutic agent in bone marrow transplantation.
- Accurate busulfan dosing is essential for therapeutic efficacy and minimizing toxicity.
- Previous dosing strategies may not be optimal for pediatric populations.
Purpose of the Study:
- To evaluate the effectiveness of busulfan dose adjustments in children undergoing bone marrow transplant.
- To determine optimal dosing parameters for busulfan in pediatric patients.
- To assess the predictability of area under the curve (AUC) from limited sampling points.
Main Methods:
- Prospective study of busulfan dosing in pediatric bone marrow transplant patients.
- Therapeutic drug monitoring using gas chromatography with electron capture detection.
- Calculation of individualized busulfan doses to achieve a target AUC of 1300 microM/min.
- Analysis of dose requirements stratified by age and body weight.
Main Results:
- Dose adjustments were necessary in 87% of evaluated busulfan courses.
- Younger children (>1 to 5 years) typically required dose increases, while older children (>5 years) often needed dose reductions.
- Busulfan concentration at 6 hours was a weak predictor of the achieved AUC (r2 = 0.496).
- Obesity did not significantly impact busulfan dose requirements.
Conclusions:
- Initial busulfan dosing in children should consider patient age and actual body weight.
- A four-sample limited sampling technique (1, 1.5, 4, and 6 hours) is recommended for calculating busulfan AUC in pediatric patients.
- Individualized busulfan dosing is critical for optimizing outcomes in pediatric bone marrow transplantation.
Abstract:
This report describes and critically appraises our experience with busulfan dose adjustment in children undergoing bone marrow transplant between April 1997 and March 1999. All children received an initial busulfan dose of 40 mg/m2 p.o. or by nasogastric tube. Whole blood samples were obtained 1, 1.5 and 6 h later and analyzed for busulfan content by gas chromatography with electron capture detection. The area under the whole blood busulfan concentration vs time curve (AUC) and an individualized dose which would achieve an AUC of 1300 microM/min were calculated. Mean and median busulfan doses were calculated using actual, ideal and effective body weight and stratified according to age. The relationship between the busulfan concentration at hour 6 and AUC was determined using linear regression. Thirty-nine courses of busulfan were evaluated in 38 patients. A change from the initial busulfan dose was required to achieve the target AUC in 34 courses (87%). Most children >1 to 5 years old required dose increments while most children >5 years old required dose reductions. Obesity did not significantly affect busulfan dose requirements. Busulfan concentrations at 6 h only weakly predicted the AUC achieved (r2 = 0.496; P = 0.001). Based on these findings, we recommend that the initial busulfan dose be assigned according to patient age and actual body weight. We also recommend that busulfan AUC be calculated for children using a four-sample (1, 1.5, 4 and 6 h) limited sampling technique.
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