Główka F K, Karaźniewicz-Łada M, Grund G, Wróbel T, Wachowiak J
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznań, Poland.
Bone Marrow Transplant. 2008 Oct;42 Suppl 2:S67-70. doi: 10.1038/bmt.2008.287.
Pharmacokinetic studies of high-dose treosulfan were carried out in seven paediatric patients (age range: 2-15 years) undergoing treosulfan-based conditioning regimen prior to allogeneic haematopoietic SCT. Treosulfan was administered intravenously in a daily dose of 10, 12 or 14 g/m(2) within 2 h. Five out of seven patients received 12 g/m(2). The plasma concentrations of treosulfan and its quantity eliminated with urine were determined using a validated HPLC method with refractometric detection. Pharmacokinetic parameters were evaluated following first dose using a two-compartment disposition model. These studies demonstrated a dose-dependent increase of area under the concentration (AUC) and maximum concentrationplasma (C(max)), but there was variability of these parameters. Rapid clearance of tresoulfan was observed, especially in 10 and 12 g/m(2) doses. Terminal half-life (t(0.5)) of treosulfan was in the range of 1.71-2.15 h, but the mean percent of parent drug eliminated with urine was 30%, range 16.3-45.4% of the total dose eliminated during the first 12 h after administration. The results of this study confirmed the linear pharmacokinetics of treosulfan, as used in children. However, variability of pharmacokinetic results observed in children studied demonstrates the need for pharmacokinetic evaluation in each paediatric patient undergoing the treosulfan-based preparative regimen, including those using different doses. This approach could enable further reduction of the risk of early and late organ toxicity related to high-dose treosulfan in paediatric patients.
在7名接受异基因造血干细胞移植且采用基于曲奥舒凡预处理方案的儿科患者（年龄范围：2至15岁）中开展了高剂量曲奥舒凡的药代动力学研究。曲奥舒凡通过静脉给药，每日剂量为10、12或14 g/m²，在2小时内输注完毕。7名患者中有5名接受了12 g/m²的剂量。采用经过验证的带折射检测的高效液相色谱法测定曲奥舒凡的血浆浓度及其经尿液消除的量。使用二室处置模型在首次给药后评估药代动力学参数。这些研究表明，浓度-时间曲线下面积（AUC）和血浆最大浓度（Cmax）呈剂量依赖性增加，但这些参数存在变异性。观察到曲奥舒凡清除迅速，尤其是在10和12 g/m²剂量时。曲奥舒凡的终末半衰期（t(0.5)）在1.71至2.15小时范围内，但给药后最初12小时内经尿液消除的母体药物平均百分比为30%，占总消除剂量的16.3%至45.4%。本研究结果证实了曲奥舒凡在儿童中使用时的线性药代动力学特征。然而，在研究的儿童中观察到的药代动力学结果变异性表明，对于每例接受基于曲奥舒凡预处理方案的儿科患者，包括使用不同剂量的患者，都需要进行药代动力学评估。这种方法可以进一步降低儿科患者中与高剂量曲奥舒凡相关的早期和晚期器官毒性风险。
