Can Published Population Pharmacokinetic Models of Busulfan Be Used for Individualized Dosing in Chinese Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation? An External Evaluation

Abstract

Busulfan is a bifunctional alkylating agent that is widely used before hematopoietic stem cell transplantation (HSCT), in combination with other chemotherapeutic drugs. As of 2020, there is no population pharmacokinetic (popPK) model for busulfan in Chinese pediatric patients. A systemic external evaluation of 11 published popPK models was conducted in Chinese pediatric patients undergoing HSCT. Forty pediatric patients were enrolled in this study, with a total of 183 blood concentrations. The relative prediction error (PE%), median PE%, median absolute PE%, and percentage of PE% within ±20% and ±30% were calculated in prediction-based diagnostics. Simulation-based diagnostics were conducted through a predictionand variability-corrected visual predictive check and the normalized prediction distribution error. The relative individual prediction error was calculated using Bayesian forecasting with 1 to 3 concentration points. The 1-compartment open linear popPK model, which was built by Su-jin Rhee et al (model H), incorporating the patient's body surface area, age, dosing day, and aspartate aminotransferase as significant covariates had preferable predictability than other popPK models. In prediction-based diagnostics, the median PE%, percentage of PE% within ±20%, and percentage of PE% within ±30% of model H were 8.48%, 45.35%, and 59.56%, respectively. The normalized prediction distribution error 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.

The Correlation Between Busulfan Exposure and Clinical Outcomes in Chinese Pediatric Patients: A Population Pharmacokinetic Study

“…However, in a recently published study ( Dunn et al, 2021 ), the typical CL for a 20 kg child was 1.14 L h −1 , which were reduced estimates compared to ours and prior studies. These discrepancies in CL might be due to published models contain various structural PK models, various covariates, different age distributions and ethnicities ( Huang et al, 2022 ).…”

“…In two recent Pop-PK studies of busulfan based on Chinese pediatric patients, BSA was considered one of the significant covariates for CL in the model developed by Yuan et al (2021) . Huang et al (2022) conducted a systemic external evaluation of 11 published models of busulfan based on an independent dataset from 40 Chinese pediatric populations and similarly concluded that a model developed from the Korean population with BSA affecting CL as one of the covariates had the most satisfactory predictability for Chinese children ( Huang et al, 2022 ). Based on children’s growth and developmental characteristics, CL in the pediatric population should be investigated using models that account for the influences of body size, maturation, and organ function.…”

“…However, the pediatric patients with these alternative Pop-PK models and dosing nomograms were mainly Caucasian ( Nguyen et al, 2004 ; Booth et al, 2007 ; Trame et al, 2011 ; McCune et al, 2014 ; Nava et al, 2018 ; van Hoogdalem et al, 2020 ), Japanese ( Nakamura et al, 2008 ; Ishiwata et al, 2018 ), and Korean ( Rhee et al, 2017 ) populations. As we know, there are a few Pop-PK studies on busulfan in Chinese adults ( Wu et al, 2017 ; Huang et al, 2019 ; Sun et al, 2020 ), and there are only two Pop-PK studies on busulfan in Chinese children ( Yuan et al, 2021 ; Huang et al, 2022 ). A systemic external evaluation of 11 published models on busulfan using data from Chinese pediatric patients by Huang et al (2022) showed that the model developed only from the Korean population ( Rhee et al, 2017 ) was suitable for Chinese HSCT pediatric patients ( Huang et al, 2022 ).…”

“…As we know, there are a few Pop-PK studies on busulfan in Chinese adults ( Wu et al, 2017 ; Huang et al, 2019 ; Sun et al, 2020 ), and there are only two Pop-PK studies on busulfan in Chinese children ( Yuan et al, 2021 ; Huang et al, 2022 ). A systemic external evaluation of 11 published models on busulfan using data from Chinese pediatric patients by Huang et al (2022) showed that the model developed only from the Korean population ( Rhee et al, 2017 ) was suitable for Chinese HSCT pediatric patients ( Huang et al, 2022 ). Therefore, due to the differences in body size, dietary habits and genetic background of the populations included in different Pop-PK studies, continued Pop-PK studies in the Chinese pediatric population are warranted to establish a platform for individualized busulfan administration.…”