Marsh Rebecca A, Fukuda Tsuyoshi, Emoto Chie, Neumeier Lisa, Khandelwal Pooja, Chandra Sharat, Teusink-Cross Ashley, Vinks Alexander A, Mehta Parinda A
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Pharmacology, Cincinnati Children's Hospital, Cincinnati, Ohio.
Biol Blood Marrow Transplant. 2017 Apr;23(4):635-641. doi: 10.1016/j.bbmt.2017.01.071. Epub 2017 Jan 12.
Alemtuzumab is frequently used as part of reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (HCT) in pediatric patients with nonmalignant diseases. We previously suggested an optimal day 0 targeted range of alemtuzumab, but there are no pediatric data regarding the pharmacokinetics (PK) of subcutaneous alemtuzumab to guide precision dosing trials. The goal of this study was to prospectively characterize alemtuzumab PK and to explore absolute lymphocyte count (ALC) as a predictor of interindividual variability. We prospectively enrolled 23 patients who received an alemtuzumab, fludarabine, and melphalan RIC regimen. Seventeen patients completed study and received 1 mg/kg alemtuzumab divided over 5 days subcutaneously, starting on day -14. The median age was 7 years (range, .5 to 18). Blood sampling for PK measurements and descriptive PK analyses were performed. The median maximum alemtuzumab concentration was 2.39 µg/mL (interquartile range, 1.98 to 2.92). The median terminal half-life was 5.2 days (interquartile range, 2.7 to 7.8). The median concentration at day 0 was 1.27 µg/mL (interquartile range, .35 to 1.51). Importantly, day 0 alemtuzumab levels and area under the curve negatively correlated with predose ALC and ALC area-time, respectively. In conclusion, we reported the PK of subcutaneous alemtuzumab given to pediatric allogeneic HCT patients and observed that almost all patients have persistence of lytic levels of alemtuzumab beyond day 0, at levels in excess of that needed to reduce the risk of acute graft-versus-host disease. Additionally, levels correlate with pretransplant ALC. These results will allow the development of population PK models for precision dosing trials.
阿仑单抗常用于非恶性疾病儿科患者异基因造血细胞移植（HCT）的减低强度预处理（RIC）方案中。我们之前提出了阿仑单抗第0天的最佳靶向范围，但尚无关于皮下注射阿仑单抗药代动力学（PK）的儿科数据来指导精准给药试验。本研究的目的是前瞻性地表征阿仑单抗的PK，并探索绝对淋巴细胞计数（ALC）作为个体间变异性的预测指标。我们前瞻性地纳入了23例接受阿仑单抗、氟达拉滨和美法仑RIC方案的患者。17例患者完成研究，从第-14天开始，皮下注射1 mg/kg阿仑单抗，分5天给药。中位年龄为7岁（范围为0.5至18岁）。进行了用于PK测量的血样采集和描述性PK分析。阿仑单抗的中位最大浓度为2.39 μg/mL（四分位间距为1.98至2.92）。中位终末半衰期为5.2天（四分位间距为2.7至7.8）。第0天的中位浓度为1.27 μg/mL（四分位间距为0.35至1.51）。重要的是，第0天的阿仑单抗水平和曲线下面积分别与给药前ALC和ALC面积-时间呈负相关。总之，我们报告了皮下注射阿仑单抗用于儿科异基因HCT患者的PK，并观察到几乎所有患者在第0天后阿仑单抗的溶解水平持续存在，其水平超过降低急性移植物抗宿主病风险所需的水平。此外，这些水平与移植前ALC相关。这些结果将有助于开发用于精准给药试验的群体PK模型。
