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Busulfan bioavailability
M Hassan1, P Ljungman, P Bolme
1Research Department, Huddinge Hospital, Stockholm, Sweden.
Insights
Busulfan bioavailability varies significantly in children and adults undergoing bone marrow transplantation. Dosage adjustments based on body surface area and drug monitoring are recommended to optimize busulfan therapy.
Area of Science:
- Pharmacology
- Oncology
- Pediatrics
Background:
- Busulfan is a key drug in myeloablative therapy for bone marrow transplantation.
- Altered busulfan disposition in children impacts treatment effectiveness and toxicity.
- Variability in drug effectiveness and toxicity necessitates further pharmacokinetic studies.
Purpose of the Study:
- To evaluate busulfan bioavailability in pediatric and adult patients.
- To compare pharmacokinetic parameters, including clearance and distribution volume, between age groups.
- To inform optimal busulfan dosing strategies in bone marrow transplantation.
Main Methods:
- Oral bioavailability assessment in two patient groups: children (1.5-6 years) and older children/adults (13-60 years).
- Intravenous administration to determine elimination half-life.
- Calculation of busulfan clearance and distribution volume normalized to body weight and body surface area.
Main Results:
- Significant interindividual variation in oral busulfan bioavailability observed in both groups.
- Busulfan clearance and distribution volume normalized to body weight were significantly higher in children than adults.
- No significant difference in clearance when normalized to body surface area, suggesting surface area as a better dosing metric.
Conclusions:
- Busulfan dosage calculation should prioritize body surface area over body weight for pediatric and adult patients.
- Individualized busulfan dose adjustments and therapeutic drug monitoring are crucial to mitigate toxicity and improve outcomes.
- Understanding pharmacokinetic differences is vital for optimizing busulfan therapy in transplantation.
Abstract:
Busulfan is widely used as a component of the myeloablative therapy in bone marrow transplantation. Recent studies have shown that the drug disposition is altered in children and is associated with less therapeutic effectiveness, lower toxicities, and higher rates of engraftment failure. We have evaluated the bioavailability of the drug in two groups of patients: eight children between 1.5 and 6 years of age and eight older children and adults between 13 and 60 years. Oral bioavailability showed a large interindividual variation. In children, the bioavailability ranged from 0.22 to 1.20, and for adults, it was within the range 0.47 to 1.03. The elimination half-life after intravenous administration in children (2.46 +/- 0.27 hours; mean +/- SD) did not differ from that obtained for adults (2.61 +/- 0.62 hours). However, busulfan clearance normalized to body weight was significantly higher in children (3.62 +/- 0.78 mL.min-1.kg-1) than that in adults (2.49 +/- 0.52 mL.min-1.kg-1). Also, the distribution volume normalized for body weight was significantly higher in children (0.74 +/- 0.10 L.kg-1) compared with 0.56 +/- 0.10 L. kg-1 in adults. The difference in clearance between children and adults was not statistically significant when normalized to body surface area, which most probably shows that busulfan dosage should be calculated on the basis of surface area rather than body weight. However, to avoid drug-related toxicities, drug monitoring and an individual dose adjustment should be considered because of the variability in busulfan bioavailability.