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09 May 2014 : Original article  

The importance of Therapeutic Drug Monitoring (TDM) for parenteral busulfan dosing in conditioning regimen for Hematopoietic Stem Cell Transplantation (HSCT) in children

Hundie TesfayeABCDEF, Romana BranovaBCD, Eva KlapkovaACD, Richard PrusaAG, Daniela JaneckovaABDE, Petr RihaADF, Petr SedlacekADF, Petra KeslovaAB, Josef MalisAB

DOI: 10.12659/AOT.889933

Ann Transplant 2014; 19:214-224

Abstract

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 AND 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 µg/L, peak levels of 849–4586 µg/L, and AUC of 2225–12818 µg/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 AUS 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.

Keywords: High Dose Busulfan Target AUC, Limited Sampling Strategy TDM, Paediatric HSCT

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Annals of Transplantation eISSN: 2329-0358
Annals of Transplantation eISSN: 2329-0358