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Published on: April 1, 2015
A Short Communication: Comparison of Methods to Estimate Busulfan Exposure in Pediatric Hematopoietic Stem Cell
Nishat Siddique1, Christine E Staatz1, Rachael Lawson2,3
1School of Pharmacy and Pharmaceutical Sciences, University of Queensland, Brisbane, Queensland, Australia.
Background:
Noncompartmental analysis (NCA) and model-based Bayesian methods (MBMs) are used for cumulative area-under-the-concentration-time curve (AUCcum) estimates during therapeutic drug monitoring. Understanding their predictive differences can assist with switching between them and result interpretation. This study aims to compare NCA-based and MBM-based busulfan-AUCcum predictions in pediatric hematopoietic stem cell transplant recipients.
Methods:
Data on busulfan (administered once daily through intermittent infusion) were obtained from 4 hospitals. Busulfan concentrations were measured 3, 3.25, 4, 5, 6, 8, and 24 hours after infusion initiation over 4 treatment days. The busulfan dose, pharmacokinetic profile, and patient covariate factors were supplied to Kinetica and InsightRX Nova using the Shukla model to generate NCA-based and MBM-based busulfan exposure predictions. Differences in AUCcum estimates at the end of the treatment course were compared using a Wilcoxon signed-rank sum test and Bland-Altman plots. The effect of restricting data to specific treatment days on the MBM-based predictions was also examined.
Results:
Data from 89 pediatric hematopoietic stem cell transplant recipients (2304 busulfan samples) were analyzed. The MBM consistently estimated higher AUCcum values than NCA, with absolute and relative percentage differences (mean ± SD) of 2.8 ± 3.1 mg·L-1·h and 3.4 ± 3.7%, respectively (P < 0.001); 1.1% of individual comparator estimates displayed a relative percentage difference ≥15%. When using the MBM and comparing sampling across all 4 days to day 1 sampling or to day 1 and 3 sampling, 14.6% and 3.4%, respectively, of estimates displayed a relative percentage difference ≥15%.
Conclusions:
When switching from NCA to MBM during therapeutic drug monitoring, a small increase in target busulfan AUCcum may be required to maintain similar drug exposure. Sampling on only day 1 may not accurately estimate AUCcum in all patients when using MBM.
