Busulfan exposure variability and acute toxicity in pediatric patients undergoing hematopoietic stem cell gene therapy.

Accurate prediction of busulfan exposure is critical to achieve target myeloablative exposure while minimizing toxicity in pediatric hematopoietic stem cell transplantation. Model-informed precision dosing is recommended for improved accuracy and flexibility; dose adjustments in clinical practice are frequently performed using linear proportionality between dose changes and area under the concentration-time curve (AUC), optionally accounting for decrease of busulfan clearance over time. We retrospectively analyzed 54 consecutive pediatric patients receiving once-daily intravenous busulfan with therapeutic drug monitoring to characterize the relationship between dose adjustments and AUC variations, and to explore determinants of acute toxicity. Correlation between dose adjustments and AUC variations was linear for dose changes up to 1.16-fold, but linearity underestimated AUC increases following larger dose escalations. A quadratic model better described the dose-AUC relationship, particularly for dose increases, and was supported by an inverse correlation between dose variation and clearance change. While cumulative AUC was consistently maintained within target ranges, higher peak single-dose AUCs were associated with increased acute toxicity, including longer duration of mucositis and greater parenteral nutrition requirements. Initial dosing at 80 mg/m2 was associated with lower peak AUCs and reduced need for subsequent dose corrections compared with 120 mg/m2, without differences in engraftment outcomes. These findings highlight the clinical relevance of non-linear dose-exposure relationships and peak exposure in busulfan-related toxicity.