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Supplementary Figure 2 from Population Pharmacokinetics of Busulfan in Children: Increased Evidence for Body Surface Area and Allometric Body Weight Dosing of Busulfan in Children

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posted on 2023-03-31, 16:47 authored by Mirjam N. Trame, Martin Bergstrand, Mats O. Karlsson, Joachim Boos, Georg Hempel

PDF file - 139KB, prediction corrected Visual Predictive Checks pcVPC; (A) development models; (B) development models with IV busulfan data; (C) development models with oral busulfan data; (D) evaluation dataset; pcVPCs show the median solid black line, 5th and 95th percentiles dashed black lines for the observed data with 95% confidence intervals for the median dark grey field, 5% and 95% percentiles light grey fields based on simulations.

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ARTICLE ABSTRACT

Purpose: To evaluate the best method for dosing busulfan in children, we retrospectively analyzed two different data sets from three different dosing regimens by means of population pharmacokinetics using NONMEM.Experimental Design: The development data set consisted of plasma samples from 94 children, in the age range of 0.4 to 18.8 years, receiving either oral or intravenous busulfan. The external model evaluation data set comprised 24 children, in the age range of 0.1 to 18.9 years, who belonged to the 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) were used to describe the results sufficiently. In addition to interindividual variability on all pharmacokinetic parameters, interoccasion variability was included for CL and V.Results: CL values in the present study 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. Furthermore, bioavailability was calculated to be between 93% and 99% for the development data set. On the basis of the final models, we simulated two dosing schemes according to allometric BW and BSA showing that we estimated to include about 30% more patients into the proposed therapeutic area under the curve (AUC) range of 900 to 1,500 μM*min and could, furthermore, achieve a reduction in the AUC variability when dosed according to the labeled European Medicines Agency (EMA) dosing recommendation.Conclusion: We recommend a BSA or an allometric BW dosing regimen for individualizing busulfan therapy in children to reduce variability in busulfan exposure and to improve safety and efficacy of busulfan treatment. Clin Cancer Res; 17(21); 6867–77. ©2011 AACR.

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