Busulfan Dosing in Children: Body Weight versus Body Surface Area or Allometric Body Weight Dosing
Mirjam N. Trame (1,3), Martin Bergstrand (2), Mats O. Karlsson (2), Joachim Boos (3), Georg Hempel (1,3)
(1) Department of Pharmaceutical and Medical Chemistry Clinical Pharmacy -, University of Münster, Germany; (2) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (3) Department of Paediatric Haematology and Oncology, University Childrens Hospital Münster, Germany
Objectives: Busulfan is frequently used in high-dose conditioning regimens prior to bone marrow transplantation in children. The aim of the current analysis was to evaluate whether the EMA dosing recommendation in the labelling of IV busulfan [Busilvex®] according to body weight [BW] is adequate for dosing busulfan in children or if more precise dosing recommendations can be suggested. Of particular interest was the comparison of the area under the curve [AUC] of a BW based dosing regimen as recommended in the labelling of Busilvex® with other dosing regimens such as a body surface area [BSA] based dosing regimen.
Methods: We retrospectively analysed two different datasets from three different dosing regimens by using NONMEM. The development dataset consisted of plasma samples from 94 children, aged 0.4-18.8 years, receiving either oral or IV busulfan. The external model evaluation dataset included 24 children, aged 0.1-18.9 years, from once-daily IV busulfan dosing regimen. A one-compartment model with first-order absorption using BSA or allometric BW as covariate on clearance [CL] and BW as covariate on volume of distribution [V] described the results sufficiently. Apart from interindividual variability on all pharmacokinetic parameters, interoccasion variability was included for CL and V. On the basis of the two final models, new dosing regimens according to BSA or allometric BW were simulated.
Results: CL values did not reflect the shape of the CL versus BW curve reported in previous investigations. By external model evaluation and simulations, using prediction corrected Visual Predictive Checks, we were able to confirm these findings. Further, bioavailability was calculated to be between 93-99% for the development dataset. Based on the final models, we simulated two dosing schemes for dosing IV busulfan according to allometric BW and BSA showing that we estimated to get about 30% more patients into the proposed therapeutic AUC range of 900-1500 µM*min and could further achieve a decrease in the AUC variability as when dosed according to the labelled EMA dosing recommendation. Furthermore, to explore the maximum theoretical benefit with TDM another simulation was performed assuming that the true CL for each individual could be assessed during the first treatment cycle. Adjusting the dose according to these individual CL values by using the new formulas resulted in 90% of the patients being within the desired AUC range of 900-1500 µM*min.
Conclusions: According to our calculations, the labelling of Busilvex® might be redeveloped for dosing IV busulfan in children in order to optimise the dose intensity. We would recommend using one of the two newly suggested dosing regimens according to each individuals BSA or allometric BW. These dosing regimens are expected to provide AUCs closer to the therapeutic target for a priori and TDM dose adjustments.