Busulfan is widely used as conditioning in allogeneic haematopoietic cell transplantation (allo-HCT) and has a narrow therapeutic range (80-100 mg*hr/L). Primary objective was to examine the effect of therapeutic drug monitoring (TDM) on attaining busulfan target exposure in children and adults undergoing allo-HCT. Secondarily, we studied potential predictors for within-person variability in busulfan clearance.
All children and adults who underwent allo-HCT with intravenous busulfan were prospectively included (July 2011 – July 2016, UMC Utrecht, NL). Busulfan was administered once daily on four consecutive days and drug levels were measured on days 1 and 4. Cumulative exposure (cAUC) and clearance were estimated using a population model. cAUCs were compared between (1) without TDM (hypothetical, e.g. four times AUC-day1), (2) actual TDM (fixed clearance over time), and (3) TDM with an adapted PK model (taking into account age and temporal changes in busulfan clearance). Potential determinants of clearance alterations were modeled using linear regression.
In the total patient population (n = 239), substantially more patients attained their busulfan target (76.2%) with TDM (adapted PK model) as compared to when no TDM would have been performed (49.8%, rate ratio 1.53, 95% confidence interval 1.21-1.93). Moreover, TDM resulted into a significantly lower variation in cAUC (-41%, p < 0.001). Age (p < 0.001) and use of paracetamol (p = 0.025) and anticonvulsants (p = 0.044) were identified as independent predictors for decline in busulfan clearance over time.
TDM is of added value in preventing severe under and over exposure of busulfan in patients undergoing allo-HCT. We strongly advocate the use of PK model aided TDM anticipating a decrease in busulfan clearance. This particularly applies to adults and individuals taking paracetamol or anticonvulsants, given the more pronounced decline in busulfan clearance observed in this subset of patients.
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All authors have declared no conflicts of interest.