A New IV Busulfan Fixed Dosing as Part of BuMel or BuCy Conditioning Regimens: A Pharmacokinetic/Pharmacodynamic Study in Pediatric Patients Undergoing Autologous or Allogeneic Hematopoietic Stem Cell Transplantation.

Background: Busulfan (Bu) given in myeloablative doses is frequently included in hematopoietic stem cell transplantation (HSCT) regimens for pediatric (Ped) patients (pts). Following administration of oral Bu, plasma concentrations versus time profiles (AUC) vary considerably. Over-exposure is correlated with higher toxicities while under-exposure is associated with graft rejection. The IV formulation of Bu is demonstrated to provide reliable dosing, reducing inter- and intra-pts pharmacokinetic (PK) variability, and thus avoiding therapeutic drug monitoring (TDM) with dose adjustments. In a previous study, a new body-weight based calculation of IV Bu fixed dose was defined to target AUC (900–1500 μM.min) in children [Nguyen L et al. BMT 2004]. The PK results of a new prospective study in children have been presented earlier [Vassal G. et al, ASCO 2005; # 8535] and we report here the results of the investigated PK vs. pharmacodynamic (PK/PD) relationships.

Methods: Children received either IVBu/Melphalan (Mel, 140 mg/m²) or IVBu/Cyclophosphamide (Cy, 200 mg/kg) before autologous (auto-) or allogeneic (allo-) HSCT, respectively. IV Bu was infused over 2 h at a dose of 1.0 mg/kg, 1.2 mg/kg, 1.1 mg/kg, 0.95 mg/kg, and 0.8 mg/kg for pts < 9 kg, 9 to < 16 kg, 16 to 23 kg, >23 to 34 kg, and >34 kg strata of weight, respectively. No dose adjustment was allowed. Bayesian Bu AUCs were calculated at doses 1, 9 and 13. The PK/PD analysis was carried out on engraftment and regimen-related toxicities (RRT).

Results: Overall, 55 pts with a median age 6 y [0.3 – 17.2], 20 pts ≤ 4 y, were enrolled: 27 and 28 received IVBuMel and IVBuCy, respectively. Bu clearance was confirmed to be widely variable (CV=50%) however the new dosing enabled homogeneous AUCs whatever the patient’s weight, and AUC inter- pts variability was hugely reduced (CV < 20%). In allo-HSCT, all AUCs were > 900 μΜ.min (threshold value for engraftment), and there was no early and/or late graft rejection. Over-exposure was limited (all AUCs < 2100 μΜ.min) and no correlation was observed with the low incidence of VOD in allo- (2/28, 7%) and auto- (4/27, 15%) pts. Of note, 87 % and 91% of AUCs in allo- and auto- pts were < 1500 μΜ.min. In auto-pts, there was a significantly positive correlation (R²=0.35, p< 0.01) between stomatitis severity and AUC. It was also illustrated that higher AUC tended to increase bilirubin value from baseline, but the correlation was weak. No significant correlations were detected with other RRT and efficacy parameters.

Conclusions: Body-weight based calculation of IV Bu fixed doses has successfully targeted a therapeutic AUC in children. The high rate of AUC targeting achieved without any PK monitoring and dose adjustment is likely to favourably contribute to the efficacy and safety in IV Bu-based HSCT regimens.