Zao Jamie H, Schechter Tal, Liu Wenchao Jessica, Gerges Sandra, Gassas Adam, Egeler R Maarten, Grunebaum Eyal, Dupuis L Lee
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacy, The Hospital for Sick Children, Toronto, Ontario, Canada.
Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Biol Blood Marrow Transplant. 2015 Aug;21(8):1471-8. doi: 10.1016/j.bbmt.2015.05.006. Epub 2015 May 11.
Achievement of a busulfan area-under-the-concentration versus time curve (AUC) of 900 to 1500 μM·min is associated with improved hematopoietic stem cell transplant (HSCT) outcomes. Multiple pediatric busulfan dosing guidelines aim to achieve this target. The authors' objective was to describe the AUCs achieved after simulated dosing using available pediatric i.v. busulfan dosing guidelines. The health records of children who received i.v. busulfan for HSCT conditioning at The Hospital for Sick Children were reviewed. Busulfan AUCs were calculated for each patient based on plasma busulfan concentrations using either a 1-compartment model or a validated limited-sampling strategy. Published pediatric busulfan dosing guidelines were identified. Initial busulfan doses were determined for all patients using each dosing guideline and total body weight (TBW). For overweight patients (TBW-to-ideal body weight [IBW] ≥ 1.25), initial busulfan doses were also determined using IBW and adjusted IBW (IBWadj). The resulting AUCs were simulated. The proportion of subjects (TBW/IBW < 1.25, TBW/IBW ≥ 1.25, and infants) with an AUC within target (900 to 1500 μM·min) after dosing simulation with each guideline was compared. One hundred eleven children (mean age, 6.2 years [SD, ±5.2]) who received i.v. busulfan were included. When dosing with each of the 12 i.v. busulfan dosing guidelines identified was simulated using TBW in 97 non-overweight patients, the proportion of patients with an AUC within the target range varied from 51% to 74% and from 45% to 64% in infants. Use of IBW or IBWadj to calculate initial busulfan doses in overweight children improved the performance of most guidelines. Current busulfan dosing guidelines vary in their ability to achieve AUCs within the target range. For children who are not overweight, we recommend 1 of 3 high-performing guidelines that allow individualization of the target busulfan AUC. Use of either IBW or IBWadj in overweight children improves the performance of most guidelines. Regardless of the guideline used, therapeutic drug monitoring is essential to verify achievement of the target AUC.
白消安浓度-时间曲线下面积（AUC）达到900至1500μM·min与改善造血干细胞移植（HSCT）结局相关。多个儿科白消安给药指南旨在实现这一目标。作者的目的是描述使用现有的儿科静脉注射白消安给药指南进行模拟给药后所达到的AUC。回顾了在病童医院接受静脉注射白消安进行HSCT预处理的儿童的健康记录。基于血浆白消安浓度，使用单室模型或经过验证的有限采样策略为每位患者计算白消安AUC。确定已发表的儿科白消安给药指南。使用每个给药指南和总体重（TBW）为所有患者确定初始白消安剂量。对于超重患者（TBW与理想体重[IBW]之比≥1.25），还使用IBW和调整后的IBW（IBWadj）确定初始白消安剂量。模拟得出的AUC。比较了使用每个指南进行给药模拟后AUC在目标范围内（900至1500μM·min）的受试者比例（TBW/IBW<1.25、TBW/IBW≥1.25和婴儿）。纳入了111名接受静脉注射白消安的儿童（平均年龄6.2岁[标准差，±5.2]）。当在97名非超重患者中使用TBW模拟确定的12种静脉注射白消安给药指南中的每一种进行给药时，AUC在目标范围内的患者比例在51%至74%之间，婴儿中的比例在45%至64%之间。在超重儿童中使用IBW或IBWadj计算初始白消安剂量可改善大多数指南的性能。当前的白消安给药指南在实现目标范围内AUC的能力方面存在差异。对于非超重儿童，我们推荐3种高性能指南中的1种，这些指南允许对白消安目标AUC进行个体化。在超重儿童中使用IBW或IBWadj可改善大多数指南 的性能。无论使用何种指南，治疗药物监测对于验证目标AUC的实现至关重要。
