Junjun Mao1, Di Cao2, Xiaowen Qian2, Ping Wang2, Xinyi Zheng1, Shan Huang3, Zhonglin Wei4, Wenjin Jiang2, Ling Yu2, Xin Jiang2, Ying Yu2, Xiaowen Zhai2
1Huashan Hospital of Fudan University, 2National Children's Medical Center, Children’s Hospital of Fudan University, 3Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 4Children's Hospital of Soochow University
Busulfan exhibits marked inter- and intra-individual pharmacokinetic/pharmacodynamic (PK/PD) variability in children, which complicates dose optimization for hematopoietic stem cell transplantation (HSCT). To address this issue, the present study characterized the factors influencing busulfan PK variability, focusing on glutathione S-transferase (GST) activity, and proposed a model-informed dosing strategy. A semi-mechanistic population PK model integrating a glutathione (GSH) depletion compartment was developed using 636 concentration-time points from 65 pediatric HSCT recipients. Body size (normal fat mass, NFM) and age-dependent maturation were allometrically scaled, while GST activity was found to exponentially influence the GSH depletion rate (SGSH). The final model estimated the busulfan clearance (CL) rate to be 9.57 L/h (relative standard error: 10.8%), with inter-occasion variability of 28.2%. GST activity significantly modulated SGSH, increasing it by 40.6% across the observed enzyme activity range (0.9-20.7 nmol/min/mL). Virtual clinical trials comparing weight- (WT) and age-based dosing revealed that patients weighing 9-16 kg receiving WT-based regimens had higher risks of sinusoidal obstructive syndrome (SOS) due to supratherapeutic busulfan maximum concentrations (>1.88 ng/mL). Conversely, age-based dosing reduced toxicity, but required Bayesian adaptive dosing to ensure therapeutic exposure (target cAUC: 78-101 mg·h/L). These findings underscore the necessity of model-informed precision dosing, integrating NFM, maturation, and GST activity, to balance efficacy and safety in pediatric HSCT.
Reference: PAGE 33 (2025) Abstr 11561 [www.page-meeting.org/?abstract=11561]
Poster: Drug/Disease Modelling - Paediatrics