Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study

Abstract

Busulfan (Bu) is a common component of conditioning regimens before hematopoietic stem cell transplantation (HSCT) and is known for high interpatient pharmacokinetic (PK) variability. This study aimed to develop and externally validate a multicentric, population PK (PopPK) model for intravenous Bu in pediatric patients before HSCT to first study the influence of glutathione-s-transferase A1 (GSTA1) polymorphisms on Bu's PK in a large multicentric pediatric population while accounting for fludarabine (Flu) coadministration and, second, to establish an individualized, model-based, first-dose recommendation for intravenous Bu that can be widely used in pediatric patients. The model was built using data from 302 patients from five transplantation centers who received a Bu-based conditioning regimen. External model validation used data from 100 patients. The relationship between body weight and Bu clearance (CL) was best described by an age-dependent allometric scaling of a body weight model. A stepwise covariate analysis identified Day 1 of Bu conditioning, GSTA1 metabolic groups based on GSTA1 polymorphisms, and Flu coadministration as significant covariates influencing Bu CL. The final model adequately predicted Bu first-dose CL in the external cohort, with 81% of predicted area under the curves within the therapeutic window. The final model showed minimal bias (mean prediction error, -0.5%; 95% confidence interval [CI], -3.1% to 2.0%) and acceptable precision (mean absolute prediction error percentage, 18.7%; 95% CI, 17.0%-20.5%) in Bu CL prediction for dosing. This multicentric PopPK study confirmed the influence of GSTA1 polymorphisms and Flu coadministration on Bu CL. The developed model accurately predicted Bu CL and first doses in an external cohort of pediatric patients.

FIGURE 1

Final model goodness‐of‐fit plots: (a) observed busulfan concentrations versus population predicted concentrations, (b) observed busulfan concentrations versus individual predicted concentrations, (c) CWRES versus time after infusion initiation, and (d) CWRES versus population‐predicted concentrations. CWRES, conditional weighted residuals

FIGURE 2

Prediction‐corrected visual predictive check of the final model using the external validation data set: (a) doses every 6 h and (b) doses every 24 h. The marks represent the observed concentrations. Red solid lines represent the 5th, 50th, and 95th percentiles of observed concentrations; dashed black lines represent the 5th, 50th, and 95th percentiles of predicted concentrations; and shaded areas represent 95% confidence intervals of the predicted 5th, 50th, and 95th percentiles. The observed data's percentiles were in concordance with the predicted data's percentiles. Bu, busulfan

FIGURE 3

(a) Accuracy and (b) precision of the model‐predicted first‐dose clearances obtained with the new glutathione‐s‐transferase A1‐based and fludarabine‐based models and other tested models. The shaded area represents the acceptance interval in terms of bias and precision. The central lines in the boxplots represent the median values. The plus signs represent the mean values. The bottom and top edges of the boxplots indicate the 25th and 75th percentiles of predicted clearance errors. The whiskers represent the full range of prediction errors. The new model exhibits better accuracy (mean prediction error closer to 0) than every model except for the Long‐Boyle model (see Table 3). The new model exhibits better precision (lowest mean absolute prediction error, error distribution within the 25% acceptance limit) than every model except for the Nava model. APE, absolute prediction error; PE, prediction error

FIGURE 4

Box plots of simulated AUCs with predicted q24h doses using the evaluated dosing guidelines on the external validation data set. The boxplot's central line represents the median. The plus sign represents the mean value. The bottom and top edges of the boxplots indicate the 25th and 75th percentiles. The whiskers represent the full range of predicted AUCs. The shaded area represents the conventional therapeutic window of busulfan. The percentage of patients within the target window and the p values from the pairwise comparison with the McNemar test for related samples are displayed below the boxes. ^aDose calculation based on nomogram, with target AUC fixed by the author as 19.7 mg·h/L for q24h doses. ^bDose calculation based on nomogram, with target AUC fixed by the author as 18.5 mg·h/L for q24h doses. AUC, area under the curve; EMA, European Medicines Agency's dose recommendation; FDA, U.S. Food and Drug Administration's dose reccomendation; q24h, every 24 h dosing; Ref., reference.