The importance of Therapeutic Drug Monitoring (TDM) for parenteral busulfan dosing in conditioning regimen for Hematopoietic Stem Cell Transplantation (HSCT) in children
Abstrakt
Background: Series of observations indicate PK/PD variability challenging the accuracy of the body-weight based busulfan (Bu) dosing schedule for (HSCT) conditioning therapy. The purpose of this communication is to describe the frequency of dose changes in initially body-weight-based fixed IV Bu dose and to emphasize the importance of TDM.
Material/Methods: Sixty-two children (ages 2 months-18 years) were treated with IV busulfan doses based on body weight for myeloablation. TDM utilizing a limited sample strategy (trough concentration immediately before the 5th dose, followed by samples immediately after the end of the 2-h infusion peak, 4 h, and 6 h from initiation of the infusion) was performed in 46 of 62 subjects.
Busulfan concentrations were determined by high-performance liquid chromatography (HPLC). AUC was calculated according to the trapezoidal rule.
Results: We observed trough levels of 25-1244 mu g/L, peak levels of 849-4586 mu g/L, and AUC of 2225-12818 mu g/L.h following body weight-based high-dose busulfan. The doses were changed in 54% of cases.
AUC in 5 of 9 patients with VOD were within target, in 3 patients AUC was higher, and in 1 patient AUC was lower. One of the 2 patients with neurotoxicity had higher AUC.
Engraftment was 100%, but relapse occurred in 25% of cases. Conclusions: Our results demonstrate that even with IV busulfan, intra-individual PK/PD variability is challenging.
Although AUC does not necessarily correspond with outcomes (due to the role of other factors the fact that doses were changed in 54% of cases underlines the importance of TDM.