Population Pharmacokinetics of Busulfan in Children: Increased Evidence for Body Surface Area and Allometric Body Weight Dosing of Busulfan in Children Running title: Population Pharmacokinetics of Busulfan in Children

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. In this article we propose new individualized busulfan dosing regimens, in order to increase safety and efficacy during busulfan therapy especially in very small children. Busulfan has a very narrow therapeutic range with higher AUC values causing a high risk of sinuosoidal obstruction syndrome of the liver and mucositis as a result of high busulfan exposure. Lower AUC values can result in an increased incidence of graft failure due to low exposure to busulfan. The labeled EMA dosing recommendation is weight-based with five dosing groups. In our population, we could not confirm the shape of the clearance versus weight relationship on which the EMA dosing recommendation is based on. Two newly developed dosing regimens according to each individual's body surface area or allometric body weight are expected to provide AUCs closer to the therapeutic target consequently increase efficacy and safety of therapy. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Purpose: To evaluate the best method for dosing busulfan in children, we retrospectively analyzed two different datasets from three different dosing regimens by means of population pharmacokinetics using NONMEM. Experimental Design: The development dataset consisted of plasma samples from 94 children, aged 0.4-18.8 years, receiving either oral or intravenous busulfan. The external model evaluation dataset included 24 children, aged 0.1-18.9 years, from once-daily intravenous busulfan dosing regimen. A one-compartment model with first-order absorption using body surface area [BSA] or allometric body weight [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. Results: CL values did not reflect the shape of the CL versus weight curve reported in previous investigations. By external model evaluation we were able to confirm these findings. Further, bioavailability was calculated to be 93-99% for the development dataset. Based on the final models we simulated two dosing schemes according to allometric BW and BSA showing that we estimated to get about 30% more patients into the proposed therapeutic area under the curve [AUC] range of 900-1500 µM*min and could further achieve a decrease in the AUC variability as when dosed according to the labeled EMA dosing recommendation. Conclusion: We suggest a BSA or an allometric BW …