Evaluatie van een geïndividualiseerd doseerschema voor busulfan bij kinderen die een allogene hematopoëtische stamceltransplantatie ondergaan

Abstract

OBJECTIVE 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.