Can Published Population Pharmacokinetic Models of Busulfan be used for Individualized Dosing in Chinese pediatric patients undergoing Hematopoietic Stem Cell Transplantation: An External Evaluation.

Busulfan (Bu) is a bifunctional alkylating agent that is widely used prior to hematopoietic stem cell transplantation (HSCT), in combination with other chemotherapeutic drugs. As of 2020, there is no population pharmacokinetic (pop PK) model for Bu in Chinese pediatric patients. A systemic external evaluation of eleven published pop PK models was conducted in Chinese HSCT pediatric patients. Forty pediatric patients were enrolled in this study, with a total of 183 blood concentrations. The relative prediction error (PE%), median PE% (MDPE), median absolute PE%, and percentage of PE% within ±20% (F20 ) and ±30% (F30 ) were calculated in prediction-based diagnostics. Simulation-based diagnostics were conducted through a prediction- and variability-corrected visual predictive check (pvcVPC) and the normalized prediction distribution error (NPDE). The relative individual prediction error (IPE%) was calculated using Bayesian forecasting with 1-3 concentration points. The one-compartment open linear pop PK model, which was built by Su-jin Rhee et al. (model H), incorporating patient's body surface area, age, dosing day, and aspartate aminotransferase as significant covariates had preferable predictability than other pop PK models. In prediction-based diagnostics, the MDPE, F20 , and F30 of model H were 8.48%, 45.35%, and 59.56%, respectively. The NPDE of model H showed that it followed the normal distribution. Based on Bayesian forecasting, model H showed good predictive performance. Thus, model H was the most appropriate model, that can be used clinically for individualized dosage adjustments in Chinese pediatric HSCT patients. This article is protected by copyright. All rights reserved.