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Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology
M Hassan1, G Oberg, A N Bekassy
1Karolinska Pharmacy, Stockholm.
Insights
Busulphan plasma levels are lower and cleared faster in young children undergoing bone marrow transplant conditioning. Dosage adjustments are needed for optimal busulphan therapy in pediatric patients.
Area of Science:
- Pharmacology
- Pediatric Oncology
- Bone Marrow Transplantation
Background:
- Busulphan is a key chemotherapeutic agent used in conditioning regimens prior to hematopoietic stem cell transplantation.
- Understanding busulphan pharmacokinetics in different age groups is crucial for optimizing treatment efficacy and minimizing toxicity.
Purpose of the Study:
- To investigate the pharmacokinetic profile of busulphan in pediatric patients undergoing bone marrow transplantation.
- To compare busulphan plasma levels, clearance, and half-life in young children versus older children and adults.
Main Methods:
- Plasma busulphan concentrations were measured in 27 patients receiving a standard conditioning regimen (1 mg/kg x 4 daily for 4 days).
- Pharmacokinetic parameters including minimal concentration, area under the curve (AUC), elimination half-life, and total body clearance were calculated.
- Data were analyzed to compare pharmacokinetic differences across age groups (young children, older children, adults).
Main Results:
- Young children (<5 years) exhibited significantly lower mean minimal plasma busulphan concentrations and AUC compared to older children and adults.
- The elimination half-life of busulphan was shorter in young children, while total body clearance was significantly higher.
- Busulphan plasma levels demonstrated circadian rhythmicity, with higher concentrations observed during nighttime, particularly in young children.
Conclusions:
- Current busulphan dosing regimens may not be optimal for young pediatric patients undergoing bone marrow transplantation.
- Significant pharmacokinetic differences in young children necessitate reconsidering busulphan dosage for this population.
- Further research is required to establish evidence-based, optimized busulphan dosing strategies for pediatric patients.
Abstract:
Busulphan levels in plasma were measured in 27 patients during conditioning therapy (1 mg/kg x 4 for 4 days) before bone marrow transplantation. The mean minimal concentration found in children aged less than 5 years (237 ng ml-1) was lower than that observed in adults or older children (607 and 573 ng ml-1, respectively). The AUC for the last dose was significantly lower in young children (2.315 h ng ml-1) than in adults or older children (6,134 and 5,937 h ng ml-1, respectively). The elimination half-life for the last dose in young children was shorter (2.05 h) than that in either adults (2.59 h) or older children (2.79 h). When the AUC was normalized for body surface area, the difference between young children and the other groups was smaller but remained statistically significant. The total body clearance was significantly higher in young children (7.3 ml min-1 kg-1) as compared with both older children and adults (3.02 and 2.7 ml min-1 kg-1, respectively). The plasma levels of busulphan showed circadian rhythmicity, especially in young children. The concentration measured during the night in some patients was up to 3-fold that observed during daytime. We conclude that the busulphan dosage for children must be reconsidered and that further studies are urgently needed to develop an optimal therapy.