CANSEARCH Research Platform in Pediatric Oncology and Hematology, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland.
Division of Pediatric Oncology and Hematology, Department of Pediatrics, Gynecology and Obstetrics, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
CPT Pharmacometrics Syst Pharmacol. 2021 Sep;10(9):1043-1056. doi: 10.1002/psp4.12683. Epub 2021 Aug 28.
Busulfan (Bu) is a common component of conditioning regimens before hematopoietic stem cell transplantation (HSCT) and is known for high interpatient pharmacokinetic (PK) variability. This study aimed to develop and externally validate a multicentric, population PK (PopPK) model for intravenous Bu in pediatric patients before HSCT to first study the influence of glutathione-s-transferase A1 (GSTA1) polymorphisms on Bu's PK in a large multicentric pediatric population while accounting for fludarabine (Flu) coadministration and, second, to establish an individualized, model-based, first-dose recommendation for intravenous Bu that can be widely used in pediatric patients. The model was built using data from 302 patients from five transplantation centers who received a Bu-based conditioning regimen. External model validation used data from 100 patients. The relationship between body weight and Bu clearance (CL) was best described by an age-dependent allometric scaling of a body weight model. A stepwise covariate analysis identified Day 1 of Bu conditioning, GSTA1 metabolic groups based on GSTA1 polymorphisms, and Flu coadministration as significant covariates influencing Bu CL. The final model adequately predicted Bu first-dose CL in the external cohort, with 81% of predicted area under the curves within the therapeutic window. The final model showed minimal bias (mean prediction error, -0.5%; 95% confidence interval [CI], -3.1% to 2.0%) and acceptable precision (mean absolute prediction error percentage, 18.7%; 95% CI, 17.0%-20.5%) in Bu CL prediction for dosing. This multicentric PopPK study confirmed the influence of GSTA1 polymorphisms and Flu coadministration on Bu CL. The developed model accurately predicted Bu CL and first doses in an external cohort of pediatric patients.
白消安（Bu）是造血干细胞移植（HSCT）前预处理方案中的常用药物，其药代动力学（PK）个体间差异较大。本研究旨在建立并验证一个多中心的白消安群体 PK（PopPK）模型，以研究 GST A1（GSTA1）多态性对大样本儿科患者白消安 PK 的影响，同时分析氟达拉滨（Flu）共给药的影响。其次，建立一个基于模型的个体化首剂量推荐方案，以便在儿科患者中广泛应用。该模型使用了来自五个移植中心的 302 例接受 Bu 预处理方案的患者的数据进行构建。使用来自另外 100 例患者的数据进行外部模型验证。体重与白消安清除率（CL）之间的关系最好通过体重模型的年龄依赖性体表面积比例来描述。逐步协变量分析确定了白消安预处理的第 1 天、基于 GSTA1 多态性的 GSTA1 代谢组和 Flu 共给药是影响 Bu CL 的重要协变量。最终模型能够很好地预测外部队列中白消安的首剂量 CL，81%的预测 AUC 落在治疗窗内。最终模型对白消安 CL 的预测显示出最小的偏差（平均预测误差为-0.5%；95%置信区间 [CI]：-3.1%至 2.0%）和可接受的精度（平均绝对预测误差百分比为 18.7%；95% CI：17.0%-20.5%）。这项多中心的 PopPK 研究证实了 GSTA1 多态性和 Flu 共给药对白消安 CL 的影响。所建立的模型能够准确预测儿科患者的白消安 CL 和首剂量。
