Center for Translational Medicine, University of Maryland School of Pharmacy, Baltimore, Maryland, USA.
Department of Pharmacy, Texas Children's Hospital, Houston, Texas, USA.
Br J Clin Pharmacol. 2022 May;88(5):2223-2235. doi: 10.1111/bcp.15151. Epub 2021 Dec 20.
The study objective was to develop a population pharmacokinetic model for busulfan to comprehensively examine drug-drug interactions in paediatric patients undergoing haematopoietic stem cell transplantation. Currently, there is limited evidence to substantiate potential drug-drug interactions with busulfan.
This retrospective study population was comprised of 250 patients receiving, on average, 0.8 mg/kg intravenous busulfan as pretreatment. All model analyses were conducted using nonlinear mixed effects modelling in Pumas v2.0. The metabolic pathways of primary interest were glutathione conjugation and cytochrome P450 (CYP) activity. Concomitant medications were categorized as CYP inhibitors, inducers or glutathione S-transferase depleters, and included in the model as conditional covariates. A bootstrap simulation and visual predictive check were conducted to qualify the final model.
The final 1-compartment model incorporates covariates of weight and age in relation to their effects on both total body clearance and volume of distribution. The estimated typical values of clearance and volume were 1.138 L/h (CI: 1.095-1.179 L/h) and 3.527 L (CI: 3.418-3.621 L), respectively. No significant changes in clearance were observed when medications that alter proposed hepatic and metabolic pathways of busulfan were coadministered.
To the best of our knowledge, this is the largest single centre study of busulfan in children and the first to quantify the maturation effect of both clearance and volume. This study could not demonstrate a difference in busulfan clearance when comparing patients who received medications that alter the glutathione S-transferase, CYP3A4 or CYP2C9 pathway to those who did not.
本研究旨在建立一个群体药代动力学模型，以全面研究接受造血干细胞移植的儿科患者中与白消安相关的药物相互作用。目前，仅有有限的证据可以证实白消安与药物相互作用的潜力。
本回顾性研究的患者群体包括 250 名接受平均 0.8mg/kg 静脉白消安预处理的患者。所有模型分析均采用 Pumas v2.0 中的非线性混合效应建模进行。主要关注的代谢途径是谷胱甘肽结合和细胞色素 P450（CYP）活性。同时给予的药物被归类为 CYP 抑制剂、诱导剂或谷胱甘肽 S-转移酶耗竭剂，并作为条件协变量纳入模型。采用 bootstrap 模拟和可视化预测检查对最终模型进行验证。
最终的 1 室模型纳入了体重和年龄的协变量，以反映它们对总清除率和分布容积的影响。估计的清除率和容积的典型值分别为 1.138L/h（CI：1.095-1.179L/h）和 3.527L（CI：3.418-3.621L）。当给予改变白消安拟议肝代谢途径的药物时，清除率没有明显变化。
据我们所知，这是最大的单一中心儿童白消安研究，也是首次定量研究清除率和容积的成熟效应。本研究未能证明当比较接受改变谷胱甘肽 S-转移酶、CYP3A4 或 CYP2C9 途径的药物与未接受这些药物的患者时，白消安清除率有差异。
