Aim: The aim of this study was to develop a population pharmacokinetic (PPK) model in Chinese children for intravenous busulfan, and to develop a novel busulfan dosing regimen to support better area under the concentration-time curve (AUC) targeting. Methods: We collected busulfan concentration-time samples from 69 children who received intravenous busulfan prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT). A population pharmacokinetic model for busulfan was developed by nonlinear mixed effect modelling and was validated by an external dataset (n=14). A novel busulfan dosing regimen was developed through simulation on 1000 patients. Limited Sampling Strategy (LSS) was established by the Bayesian forecasting. Absolute Prediction Error (APE), Mean Absolute Prediction Error (MAPE) and relative Root Mean Squared Error (rRMSE) were calculated to evaluate predictive accuracy. Results: A one-compartment model with first-order elimination best described the data. GSTA1 genotypes, BSA and AST were found to be significant covariates of Bu clearance, and BSA had remarkable impact of the volume. Moreover, recommended dose regimens for children with different GSTA1 genotypes and BSA were developed with a perfect AUC targeting. A two-point LSS, two hours and four hours after dosing, behaved well with acceptable prediction precision. Conclusion: This study developed a PPK model for busulfan that firstly incorporated GSTA1 genotypes in an Asian pediatric population. We recommend a BSA-based dosing for personalizing busulfan therapy in pediatric population. Additionally, an optimal LSS (C2h and C4h) provides convenience for therapeutic drug monitoring (TDM) in the future.

Aims This study aimed to develop a parent-metabolite joint population pharmacokinetic model to characterize the pharmacokinetic (PK) profile for phosphocreatine (PCr) and its metabolite creatine (Cr) in children with myocarditis, and to use this model to study the PK profile of different dosing schemes. Methods One hundred pediatric patients with myocarditis were enrolled. Blood samples were collected at baseline and, approximately 30, 40 or 50, 75 and 180 min after a single dose of phosphocreatine sodium. Plasma PCr and Cr concentrations were determined using a HPLC-MS/MS method. A nonlinear mixed-effects model approach was used to build the population pharmacokinetic model. After validation, the model was used for simulations to evaluate the PK profile of different dosing schemes. Results A total of 997 plasma concentrations (498 for PCr and 499 for Cr) were included in the analysis. A four-compartment chain model (central and peripheral compartments for both PCr and Cr) with first-order elimination adequately characterized the in vivo process of PCr and Cr. Allometric scaling based on bodyweight was applied to the PK parameters. The covariate analysis identified that the glomerular filtration rate (GFR) was strongly associated with the Cr clearance. Bootstrap and visual predictive check suggested a robust and reliable pharmacokinetic model was developed. The simulation results showed that the PCr had no accumulation in vivo. With the infusion of PCr, the concentration of Cr increased rapidly. Conclusion The joint population pharmacokinetic model for PCr and Cr in pediatric patients with myocarditis was successfully developed for the first time.