Ten Brink Marloes H, Ackaert Oliver, Zwaveling Juliëtte, Bredius Robbert G M, Smiers Frans J, den Hartigh Jan, Lankester Arjan C, Guchelaar Henk-Jan
*Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center; †LAP&P Consultants; and ‡Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
Ther Drug Monit. 2014 Aug;36(4):465-72. doi: 10.1097/FTD.0000000000000047.
High-dose treosulfan is used in conditioning regimens before hematopoietic stem cell transplantation in children. Pharmacokinetic data to optimize treosulfan dosing are scarce in this patient population. The aims of this study were the development and validation of an analytical method for treosulfan in human serum and the development of a pharmacokinetic model for treosulfan in pediatric patients. Furthermore, we aimed to develop a limited sampling strategy to estimate treosulfan systemic exposure with a minimum of inconvenience and risk for the patient.
A reversed phase high-performance liquid chromatography method using ultraviolet detection to determine treosulfan in human serum samples was developed and validated according to food and drug administration guidelines. Serum pharmacokinetics after the first treosulfan administration was investigated in 20 children using nonlinear mixed-effect modeling, and a limited sampling strategy was developed and validated.
The assay was validated in a 10-500 mg/L concentration range with a lower limit of quantification of 10 mg/L. Accuracies were within the 90%-110% limit. The coefficients of variation of the within-day imprecision and between-days imprecision were less than 5%. Pharmacokinetics was adequately described with a 1-compartment model. The population estimates for clearance (CL) and volume of distribution were 6.85 L/h and 13.2 L for a typical patient of 20 kg, respectively. Treosulfan exposure could be adequately quantified with 2 samples, at 4 and 7 hours after the start of a 3-hour treosulfan infusion, with a mean deviation of 3% of individual CL and area under the curve based on limited sampling in comparison with the full data set in a total cohort.
In this study, a bioanalytical method, PK model, and limited sampling model were developed and validated. Furthermore, PK parameters of 20 pediatric patients were analyzed, demonstrating an interpatient variability in area under the curve of 14.5%. This study demonstrates the essential developments in the optimization of treosulfan therapy based on PK data.
大剂量苏消安用于儿童造血干细胞移植前的预处理方案。在该患者群体中，缺乏用于优化苏消安给药剂量的药代动力学数据。本研究的目的是开发并验证一种测定人血清中苏消安的分析方法，以及建立儿科患者中苏消安的药代动力学模型。此外，我们旨在制定一种有限采样策略，以最少的不便和患者风险来估计苏消安的全身暴露量。
根据食品药品监督管理局的指导原则，开发并验证了一种采用紫外检测的反相高效液相色谱法，用于测定人血清样本中的苏消安。使用非线性混合效应模型对20名儿童首次给予苏消安后的血清药代动力学进行了研究，并制定并验证了一种有限采样策略。
该检测方法在10 - 500 mg/L浓度范围内得到验证，定量下限为10 mg/L。准确度在90% - 110%范围内。日内不精密度和日间不精密度变异系数均小于5%
。药代动力学可用单室模型充分描述
。对于一名典型的20 kg患者，清除率（CL）和分布容积的群体估计值分别为6.85 L/h和14.5 L。在3小时苏消安输注开始后4小时和7小时采集2个样本，即可充分定量苏消安暴露量，与整个队列的完整数据集相比，基于有限采样的个体CL和曲线下面积的平均偏差为
3%。
在本研究中，开发并验证了一种生物分析方法、药代动力学模型和有限采样模型。此外，分析了20名儿科患者的药代动力学参数，显示曲线下面积的患者间变异性为14.5%。本研究证明了基于药代动力学数据优化苏消安治疗的重要进展。
