Choong Eva, Uppugunduri Chakradhara Rao Satyanarayana, Marino Denis, Kuntzinger Melanie, Doffey-Lazeyras Fabienne, Lo Piccolo Rodolfo, Chalandon Yves, Peters Christina, Daali Youssef, Ansari Marc
CANSEARCH Research Laboratory, Department of Pediatrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Onco-Hematology Unit, Department of Pediatrics, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
Ther Drug Monit. 2018 Feb;40(1):84-92. doi: 10.1097/FTD.0000000000000468.
Busulfan (Bu) is an alkylating agent used as part of the conditioning regimen in pediatric patients before hematopoietic stem cell transplantation. Despite intravenous (IV) administration and dosing recommendations based on age and weight, reports have revealed interindividual variability in Bu pharmacokinetics and the outcomes of hematopoietic stem cell transplantation. In this context, adjusting doses to Bu's narrow therapeutic window is advised. We aimed to assess the utility of therapeutic drug monitoring (TDM) of Bu in children, the reliability of Bu quantification methods, and its stability in plasma when stored for up to 5 years.
Eighteen patients from our TDM center (252 samples) were included. All of them received a 2-hour Bu IV infusion 4 times daily for a total of 16 doses. The first dose of Bu was age/weight-based, and the subsequent doses were adjusted from third or fifth dose onward based on the estimated first dose pharmacokinetic parameters to target steady-state concentrations (Css) of 600-900 ng/mL. The performance of our unit's high-performance liquid chromatography with tandem mass spectrometry method was assessed using a quality control (QC, 35 series) chart. International, multicenter, cross-validation test (n = 21) was conducted to validate different analytical methods. To assess Bu stability, regression analyses and Bland-Altman plots were performed on measurements at repeated time points on samples stored at -80°C for up to 5 years.
We observed a 4.2-fold interindividual variability in Bu Css after the first dose, with only 28% of children having a Css within the target range. During the 4 days of conditioning, 83% of children had their doses modified according to TDM recommendations. This achieved a Css within the target range in 75% of the children. Routine QC measurements were generally within the ±15% range around theoretical values, showing the optimal robustness of our center's analytical method. Two of the 21 Bu TDM centers returned inadequate results during cross-validation testing; both used a UV detection method. Storage at -80°C led to a fall in Bu content of 14.9% ± 13.4% at 2-4 years and of 20% ± 5% by 5 years (roverall = 0.92).
We conclude that TDM is an effective method of achieving targeted Bu levels in children. QC programs are crucial to monitoring and maintaining the quality of an analytical method.
白消安（Bu）是一种烷化剂，用于小儿造血干细胞移植前预处理方案。尽管有基于年龄和体重的静脉注射（IV）给药及剂量建议，但报告显示，白消安的药代动力学及造血干细胞移植结果存在个体差异。在此背景下，建议根据白消安狭窄的治疗窗调整剂量。我们旨在评估儿童白消安治疗药物监测（TDM）的效用、白消安定量方法的可靠性及其在血浆中储存长达5年时的稳定性。
纳入我们TDM中心的18例患者（252份样本）。他们均接受每日4次、每次2小时的白消安静脉输注，共16剂。首剂白消安基于年龄/体重给药，后续剂量从第三或第五剂起根据首剂药代动力学参数估计值进行调整，以使稳态浓度（Css）达到600 - 900 ng/mL。使用质量控制（QC，35个系列）图评估我们科室的高效液相色谱 - 串联质谱法的性能。进行国际多中心交叉验证试验（n = 21）以验证不同的分析方法。为评估白消安的稳定性，对储存在-80°C长达5年的样本在重复时间点的测量值进行回归分析和布兰德 - 奥特曼图分析。
首剂后，我们观察到白消安Css存在4.2倍的个体差异，只有28%的儿童Css在目标范围内。在预处理的4天中，83%的儿童根据TDM建议调整了剂量。这使得75%的儿童Css在目标范围内。常规QC测量结果通常在理论值±15%范围内，表明我们中心的分析方法具有最佳稳健性。21个白消安TDM中心中有2个在交叉验证测试中结果不合格；两者均使用紫外检测法。储存在-80°C导致2 - 4年时白消安含量下降14.9%±13.4%，到第5年下降20%±5%（总体r = 0.92）。
我们得出结论，TDM是在儿童中实现白消安目标水平的有效方法。QC程序对于监测和维持分析方法的质量至关重要。
