Determination of a Limited Sampling Strategy for IV Busulfan Dose Individualization in Children.

Busulfan doses are individualized in order to achieve an area under the plasma Busulfan concentration vs time curve (AUC) to ensure engraftment while preventing hepatic venous occlusive disease. We currently calculate AUC using 7 plasma Busulfan samples drawn after the first of 16 Busulfan doses given every 6 hours. The objective of this retrospective study was to evaluate the extent of agreement between the AUC calculated using 7 plasma Busulfan concentrations (AUC-7) and each possible limited sampling strategy (LSS) in children undergoing haematopoietic stem cell transplant. 44 children aged 0.3 to 16 years (median: 3.0 years) received IV Busulfan from April 1, 2003 through January 2006 at our institution. Busulfan doses given and subsequent plasma Busulfan concentrations were recorded for each patient. AUC-7 and AUC using all possible LSSs were calculated using non-compartmental and 1-compartmental methods (WinNonLin version 5.0.1). Based on a target AUC of 1300 micromole·min/L, a theoretical adjusted Busulfan dose was calculated using AUC-7 and all LSSs using 2 and 3 plasma Busulfan concentrations. Extent of agreement between

1. the AUC-7 values and the LSS AUC values and

2. the theoretical adjusted Busulfan dose based on the AUC-7 values and the 2 and 3 point LSS AUC values was assessed by determination of the intraclass correlation coefficient (ICC; parallel, one-way random effect model) and Bland-Altman (BA) analysis.

Agreement was observed between AUC-7 calculated using non-compartmental and 1-compartmental methods and LSSs using 2 and 3 plasma Busulfan concentrations. AUC values calculated using 6 LSSs each consisting of 3 plasma Busulfan concentrations achieved ICC values > 0.96 (p<0.001) and were within the BA limits of agreement. Agreement between the theoretical Busulfan adjusted doses (7-point vs 3-point strategies) was very strong when the Busulfan concentrations obtained at the following time points were used: end of the 2 hour infusion, 3, and 4 hours after completion of the infusion; or 0.25, 3, and 4 hours after completion of the infusion. We conclude that there is excellent agreement between

1. AUC-7 and a LSS for calculation of Busulfan AUC using 3 time points and

2. between theoretical adjusted Busulfan doses calculated using AUC-7 and using these strategies.

The LSSs described here must be validated in a prospective study.