Simulation-Based Optimization of Sampling Schedules for Model-Informed Precision Dosing of Once-Daily and 4-Times-Daily Busulfan in Pediatric Patients.

Abstract

Background: Therapeutic drug monitoring (TDM) is crucial in optimizing the outcomes of hematopoietic stem cell transplantation by guiding busulfan (Bu) dosing. Limited sampling strategies show promise for efficiently adjusting drug doses. However, comprehensive assessments and optimization of sampling schedules for Bu TDM in pediatric patients are limited. We aimed to establish optimal sampling designs for model-informed precision dosing (MIPD) of once-daily (q24h) and 4-times-daily (q6h) Bu administration in pediatric patients.

Methods: Simulated data sets were used to evaluate the population pharmacokinetic model-based Bayesian estimation of the area under the concentration-time curve (AUC) for different limited sampling strategy designs. The evaluation was based on the mean prediction error for accuracy and root mean square error for precision. These findings were validated using patient-observed data. In addition, the MIPD protocol was implemented in the Tucuxi software, and its performance was assessed.

Results: Our Bayesian estimation approach allowed for flexible sampling times while maintaining mean prediction error within ±5% and root mean square error below 10%. Accurate and precise AUC0-24h and cumulative AUC estimations were obtained using 2-sample and single-sample schedules for q6h and q24h dosing, respectively. TDM on 2 separate days was necessary to accurately estimate cumulative exposure, especially in patients receiving q6h Bu. Validation with observed patient data confirmed the precision of the proposed limited sampling scenarios. Implementing the MIPD protocol in Tucuxi software yielded reliable AUC estimations.

Conclusions: Our study successfully established precise limited sampling protocols for MIPD of Bu in pediatric patients. Our findings underscore the importance of TDM on at least 2 occasions to accurately achieve desired Bu exposures. The developed MIPD protocol and its implementation in Tucuxi software provide a valuable tool for routine TDM in pediatric hematopoietic stem cell transplantation.