Variability of busulfan area under the concentration-time curve in children with different hematologic disorders

Abstract

Purpose

Limited data on the effect of hematologic disorders on the busulfan (Bu) pharmacokinetics in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) is available to date. This study aimed to investigate pharmacokinetic characteristics after the first Bu infusion in children with different hematologic disorders.

Methods

A total of 172 Bu concentrations from 43 patients with HSCT and their demographics and characteristics were included to investigate the correlations between different hematologic disorders and Bu concentration or area under the concentration time curve (AUC) using univariate and multivariate regression analysis.

Results

Bu concentration and AUC after the first dose were significantly higher in patients with leukemia than in patients with non-malignant hematologic disorders (NMHD) (P < 0.001). A high variability was observed with 14 (53.8%) of Bu AUC lower than 900 µM × min (3.69 mg × h/L) in patients with NMHD and 15 (88.2%) of Bu AUC higher than 1350 µM × min (5.54 mg × h/L) in patients with leukemia. In univariate analysis, concomitant use of glucocorticoids affected Bu AUC (P < 0.001). The Bu AUC was significantly correlated with alanine transaminase (P = 0.004), total bile acids (P = 0.003) and total bilirubin (P < 0.001). However, hematologic disorders was the only independent influencing factor of Bu AUC variation, after adjusting for the above variables.

Conclusion

Variability in Bu AUC was related to hematologic disorders of children with HSCT, which requires therapeutic drug monitoring and dose adjustment. Different phenotypes of patients should be considered when developing individualized Bu dosing regimen.