4 research outputs found
Evaluation of an individualized dosing regimen of busulfan in children undergoing allogeneic haematopoietic stem cell transplantation
Get PDFOBJECTIVE To assess target attainment of busulfan exposure using a new model-based dosing regimen and therapeutic drug monitoring (TDM). Busulfan is an alkylating drug used in conditioning regimens for allogeneic haematopoietic cell transplantation (allo-HCT). Its narrow therapeutic range in combination with large interindividual variability in exposure, even after intravenous administration, necessitates dose individualization. DESIGN Prospective cohort study. METHODS All children who underwent allo-HCT in 2011 or 2012 receiving busulfan-based conditioning were included. Intravenous busulfan was administered once daily on four consecutive days and drug levels were measured on days 1 and k. For each patient a 'hypothetical' exposure (cAUC) without TDM was determined by extrapolating the AUC of day 1. The 'true' cAUC was then estimated based on pharmacokinetic data obtained on days 1-4 including TDM-based dose adjustment. Means and ranges were compared between cAUCs determined with and without TDM-based dose corrections. Also target attainment rates (cAUC 80-100 mg-h/L] were compared between 'hypothetical' and 'true' exposure. RESULTS 50 patients were included. Without TDM mean cAUC was 85.3 mg-h/L versus 96.2 mg-h/L with TDM. The range in individual cAUCs was significantly larger without TDM than with TDM IP = 0.001 ). Without TDM 34% of patients reached target cAUC and with TDM this significantly increased to 70% of patients (P = 0.0011. CONCLUSION The weight-based dosing regimen overall led to a mean busulfan exposure within the target range, yet the interindividual variation was substantial. Therefore, TDM of intravenous busulfan remains recommended and is of utmost importance to reach optimal target exposure in order to optimize HCT outcomes
Busulfan exposure associated with event-free survival in children after allogeneic haematopoietic stem cell transplantation: A retrospective multicenter cohort study
Get PDFBusulfan exposure associated with event-free survival in children after allogeneic haematopoietic stem cell transplantation: A retrospective multicenter cohort study OBJECTIVE To determine the relationship between busulfan cumulative area under the curve (AUC] and event-free survival lEFS] in children undergoing allogeneic haematopoietic stem cell transplantation (alloHCT). DESIGN Retrospective, multicenter cohort study. METHODS Children who underwent alloHCT in 15 different centres worldwide were included in this study (2000-20131. Participants had to be on intravenous busulfan and pharmacokinetic samples had to be available. Exposure of interest was the cumulative AUC of busulfan, and primary outcome was EFS (time to graft failure, relapse or all-cause mortality). Cox regression models were used to derive relative risks (RR), and the optimal busulfan AUC level was estimated using propensity adjusted Weibull models. RESULTS A total of 674 subjects (41[%] malignant, 59[%] non- malignant) with a median age of 4.5 years (interquartile range 1.4-10.7 years) were included in the analysis. We observed a significant U-shaped relationship between busulfan cumulative AUC and EFS (P = 0.011). The optimal target was estimated at 90 mgh/L (78-101 mgh/L), and was independent of any of the investigated patient characteristics. An AUC below the target increased the risk of graft failure and relapse (relative risk 1.75, P = 0.004), while transplant-related mortality was more pronounced when the AUC was too high (relative risk 2.99, P <0.0011. CONCLUSION This is the largest study on the relationship between busulfan and clinical outcomes in children undergoing alloHCT. Our results strongly advocate the use of therapeutic drug monitoring of busulfan, using 90 mg-h/L (78-101 mg h/L) as a target
