Trough level monitoring of intravenous busulfan to estimate the area under the plasma drug concentration–time curve in pediatric hematopoietic stem cell transplant recipients

Optimizing systemic busulfan exposure, the area under the concentration–time curve (AUC), improves the outcomes for hematopoietic stem cell transplantation (HSCT). The AUC is conventionally calculated using six plasma concentrations (AUC_0–∞) drawn after the first of 16 intravenous busulfan doses given as a 2-h infusion every 6 h. The aim of the present study was to develop limited sampling strategies using three or fewer busulfan concentrations to reliably calculate AUC_0–∞ in patients undergoing HSCT. We investigated the pharmacokinetics of busulfan 46 times in 29 pediatric patients receiving intravenous busulfan. Limited sampling strategies using one, two, or three plasma busulfan concentrations were developed by multiple linear regression that showed excellent agreement with AUC_0–∞. In single-point sampling strategies, the AUC_0–∞ predicted based on C₆ (trough level: busulfan plasma concentration 6 h after the start of the infusion) was significantly correlated with, and not statistically different from, actual values as follows: AUC_0–∞ = 2556.5 C₆ + 320.9 (r ²  = 0.929, P < 0.0001, mean bias 0.282 %, precision 7.91 %). In contrast, the predicted AUCs derived from the other sampling single points did not meet the criteria. The trough level well correlated with actual AUC_0–∞, suggesting that this time-point is acceptable for busulfan monitoring.