Univ Lyon, Université Lyon 1, UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Villeurbanne, France.
Université de Monastir, Faculté de Pharmacie, Monastir, Tunisia.
Clin Pharmacokinet. 2020 Aug;59(8):1049-1061. doi: 10.1007/s40262-020-00877-z.
Busulfan therapeutic drug monitoring (TDM) is necessary to better achieve the target exposure in children before hematopoietic stem cell transplantation (HSCT). However, TDM-based dosing may be challenging if intra-individual pharmacokinetic variability (also denoted inter-occasion variability [IOV]) occurs during therapy.
The objectives of this study were to describe and quantify busulfan IOV in children, and to investigate its potential determinants.
We performed a new analysis of published data from children who received intravenous busulfan over 4 days before HSCT. We calculated individual pharmacokinetic parameters on each day of therapy using a published population pharmacokinetic model of busulfan and analyzed their changes. Population estimation of IOV was also performed with non-linear mixed effects (NLME) modeling. Potential predictors of significant decrease in busulfan clearance (CL) were assessed by using machine learning approaches.
IOV could be assessed in 136 children. Between day (D) 1 and D2, most patients (80%) experienced a decrease in busulfan CL, with a median change of - 7.9%. However, both large decreases (minimum, - 48.5%) and increases in CL (maximum, + 44%) were observed. Over D1-D3 of therapy, mean CL significantly decreased (- 15%), with a decrease of ≥ 20% in 22% of patients. Some patients also showed unstable CL from day to day. NLME modeling of IOV provided a coefficient of variation of 10.6% and 13.1% for volume of distribution (V) and CL, respectively. Some determinants of significant decreases in busulfan CL were identified, but predictive performance of the models was limited.
Significant busulfan intra-individual variability may occur in children who receive a HSCT and is hardly predictable. The main risk is busulfan overexposure. Performing TDM repeatedly over therapy appears to be the best way to accurately estimate busulfan exposure and perform precision dosing.
在进行造血干细胞移植（HSCT）之前，为了更好地达到目标暴露量，有必要对儿童进行白消安治疗药物监测（TDM）。然而，如果在治疗过程中出现个体内药代动力学变异性（也称为偶发变异性[IOV]），则基于 TDM 的剂量可能会具有挑战性。
本研究的目的是描述和量化儿童白消安的 IOV，并探讨其潜在决定因素。
我们对接受静脉注射白消安 4 天以上的 HSCT 前儿童的已发表数据进行了新的分析。我们使用白消安的已发表群体药代动力学模型在治疗的每一天计算个体药代动力学参数，并分析其变化。还使用非线性混合效应（NLME）模型进行了 IOV 的群体估算。使用机器学习方法评估了导致白消安清除率（CL）显著下降的潜在预测因子。
我们可以评估 136 名儿童的 IOV。在 D1 到 D2 之间，大多数患者（80%）经历了白消安 CL 的下降，中位数变化为-7.9%。然而，观察到 CL 的大幅度下降（最小值为-48.5%）和增加（最大值为+44%）。在整个治疗期间，D1-D3 的平均 CL 显著下降（-15%），22%的患者 CL 下降≥20%。一些患者每天的 CL 也不稳定。IOV 的 NLME 模型分别提供了分布容积（V）和 CL 的变异系数为 10.6%和 13.1%。确定了导致白消安 CL 显著下降的一些决定因素，但模型的预测性能有限。
接受 HSCT 的儿童可能会出现明显的白消安个体内变异性，且难以预测。主要风险是白消安暴露过度。在治疗过程中反复进行 TDM 似乎是准确估计白消安暴露量和进行精准剂量的最佳方法。
