Cao Di, Qian Xiaowen, Wang Ping, Zheng Xinyi, Huang Shan, Wei Zhonglin, Jiang Wenjin, Yu Ling, Jiang Xin, Yu Ying, Mao Junjun, Zhai Xiaowen
Medical Affairs Office, National Children's Medical Center, Children's Hospital of Fudan University, Shanghai, China.
Department of Hematology, National Children's Medical Center, Children's Hospital of Fudan University, Shanghai, China.
Front Pharmacol. 2025 Aug 29;16:1632588. doi: 10.3389/fphar.2025.1632588. eCollection 2025.
Busulfan is known for its high inter- and intra-individual pharmacokinetics/pharmacodynamics (PK/PD) variability, especially in children. Therefore, we aimed to identify factors affecting PK variability of busulfan in pediatric allogeneic hematopoietic cell transplantation (HCT) recipients and investigate the effect of glutathione S-transferase (GST) activity on busulfan metabolism using a semi-mechanistic population PK model.
Overall, 636 whole-blood busulfan concentrations from 65 pediatric HCT recipients were analyzed using nonlinear mixed-effects modeling. A semi-mechanistic population PK model was developed to describe busulfan metabolism in response to glutathione (GSH) depletion. The effects of potential covariates were selected based on previous study and physiologically-based theoretical mechanisms. Virtual clinical trials were conducted to compare different dosing strategies, and model-based optimal dosing regimen was recommended.
A two-compartment model with first-order absorption was selected to describe busulfan PK. A GSH compartment was added to represent the relative amount of GSH available at any time. The estimated mean clearance of busulfan was 9.57 L h (relative standard error: 10.8%). Busulfan disposition was best described by including normal fat mass (NFM) allometrically and GST enzyme activity on S exponentially. The S increased by 40.6% as GST enzyme activity increased from 0.9 nmol/min/mL to 20.7 nmol/min/mL. Patients with weights (WT) of 9-16 kg are at high risk of sinusoidal obstructive syndrome (SOS) when receiving WT-based dosing strategy.
NFM, age-dependent maturation function, and GST enzyme activity may contribute to busulfan PK variability. The WT-based dosing strategy showed a higher risk of SOS than the age-based dosing strategy in 9-16 kg patients.
白消安以其个体间和个体内药代动力学/药效学（PK/PD）高度变异性而闻名，尤其是在儿童中。因此，我们旨在确定影响小儿异基因造血细胞移植（HCT）受者白消安PK变异性的因素，并使用半机制群体PK模型研究谷胱甘肽S-转移酶（GST）活性对白消安代谢的影响。
总体而言，使用非线性混合效应模型分析了65名小儿HCT受者的636份全血白消安浓度。开发了一个半机制群体PK模型来描述白消安在谷胱甘肽（GSH）消耗情况下的代谢。基于先前的研究和基于生理学的理论机制选择潜在协变量的影响。进行虚拟临床试验以比较不同的给药策略，并推荐基于模型的最佳给药方案。
选择具有一级吸收的二室模型来描述白消安的PK。添加了一个GSH室以表示随时可用的GSH的相对量。白消安的估计平均清除率为9.57 L/h（相对标准误差：10.8%）。通过按比例包含正常脂肪量（NFM）和指数形式的GST酶活性可以最好地描述白消安的处置。随着GST酶活性从0.9 nmol/min/mL增加到20.7 nmol/min/mL，S增加了40.6%。体重（WT）为9-16 kg的患者在接受基于WT的给药策略时发生窦性阻塞综合征（SOS）的风险较高。
NFM、年龄依赖性成熟功能和GST酶活性可能导致白消安PK变异性。在9-16 kg的患者中，基于WT的给药策略比基于年龄的给药策略显示出更高的SOS风险。
