Prospective Validation of a Busulfan Pharmacokinetic Model in Children: Therapeutic Drug Monitoring Remains of Utmost Importance to Optimize Outcomes of HCT

Busulfan (Bu) is an alkylating drug used in conditioning regimens for hematopoietic cell transplantation (HCT). Optimal myelo-ablative exposure of Bu is assumed to be 90 mg*h/L when given in combination with fludarabine leading to optimal (event free) survival rates. Despite the availability of intravenous Bu instead of the oral formulation, there is still wide inter-individual variability in Bu pharmacokinetics after intravenous administration, particularly in children. An individual dosing nomogram based on a pharmacokinetic (PK) model has been developed by Bartelink et al (Clin Pharmacokinet 2012) that is expected to result in more predictive Bu exposure and thereby to a safer and more effective conditioning regimen. The aims of this study are to (i) prospectively investigate target attainment of the dosing nomogram and (ii) assess the additive value of therapeutic drug monitoring (TDM).

Methods

Bu was administered once daily in a 3-hour infusion on 4 consecutive days. Drug levels were measured on day 1 and 4 and Bu exposure was calculated as cumulative area under the concentration-time curve day 1-4 (cAUC) using MWPharm 3.60. The accuracy and precision of the dosing nomogram was assessed by comparing cAUC based only on model prediction (90 mg*h/L) with the observed cAUC for each individual patient based on PK data on day 1 (No TDM). Without TDM cAUC was calculated based on PK data on day 1 extrapolated to day 1-4. With TDM cAUC was determined on PK data on day 1 and 4, including dose adjustment. To assess the additive value of TDM the percentage patients within target cAUC 80 – 100 mg*h/L were compared for the situation that no TDM would be performed and the situation with TDM.

Results

50 consecutive pediatric HCT patients (age 3 months – 18 year) were included between 2011 and 2012. Bu exposure for each patient is shown in figure 1. Without TDM mean cAUC is 85,3 mg*h/L, this corresponds well with the predicted cAUC of 90 mg*h/L based on the PK model. The range of cAUC for individual patients however is very large (table 1). Without TDM only 34% of patients reached target cAUC and with TDM this was 70% of patients.

Table 1: pharmacokinetic data of intravenous busulfan

	No TDM n = 50	TDM n = 50
cAUC, mean (range) in mg*h/L	85.3 (45 – 156)	96.2 (74 – 117)
Patients within target cAUC 80 - 100 mg*h/L, n (%)	17 (34%)	35 (70%)

A total exposure of 90 mg*h/L relates to 21.6 mM*min total, or 5400 μM*min/day

Conclusions

This prospective validation shows that the bodyweight based dosing nomogram overall leads to a mean Bu exposure of 90 mg*h/L in patients between 3 months and 18 years. Some remaining unexplained variability between patients and between days, however, still leads to variability in exposure. Therefore TDM of intravenous Bu is still needed and of utmost importance to reach optimal target exposure in pediatric patients in order to optimize outcomes of HCT.

Figure 1: busulfan exposure for each patient