Cho Y K, Sborov D W, Lamprecht M, Li J, Wang J, Hade E M, Gao Y, Tackett K, Williams N, Benson D M, Efebera Y A, Rosko A E, Devine S M, Poi M, Hofmeister C C, Phelps M A
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
Clin Pharmacol Ther. 2017 Sep;102(3):511-519. doi: 10.1002/cpt.644. Epub 2017 May 26.
High-dose melphalan followed by autologous stem cell transplantation remains the standard of care for eligible patients with multiple myeloma, but disease response and toxicity, including severe mucositis, varies among patients. Our randomized trial investigated duration of cryotherapy (2 and 6 h) for reduction of mucositis prevalence and severity and explored factors associated with variability in pharmacokinetics and outcomes from melphalan therapy. The results demonstrate that 2-h is at least as effective as 6-h cryotherapy in decreasing severe mucositis. From a population pharmacokinetic model, we identified that fat-free mass, hematocrit, and creatinine clearance were significant covariates, as reported previously. Furthermore, we observed the rs4240803 SLC7A5 polymorphism was significantly associated with pharmacokinetic variability, and pharmacokinetics was associated with both mucositis and neutropenia. However, melphalan exposure was not associated with progression-free or overall survival in our dataset. These findings contribute to ongoing efforts to personalize melphalan dosing in transplant patients.
大剂量美法仑联合自体干细胞移植仍是适合的多发性骨髓瘤患者的标准治疗方案，但疾病反应和毒性，包括严重的粘膜炎，在患者之间存在差异。我们的随机试验研究了冷冻疗法的持续时间（2小时和6小时）对降低粘膜炎患病率和严重程度的影响，并探讨了与美法仑治疗的药代动力学变异性和结果相关的因素。结果表明，在减少严重粘膜炎方面，2小时的冷冻疗法至少与6小时的冷冻疗法一样有效。从群体药代动力学模型中，我们确定无脂肪体重、血细胞比容和肌酐清除率是显著的协变量，如先前报道。此外，我们观察到rs4240803 SLC7A5基因多态性与药代动力学变异性显著相关，并且药代动力学与粘膜炎和中性粒细胞减少均相关。然而，在我们的数据集中，美法仑暴露与无进展生存期或总生存期无关。这些发现有助于正在进行的针对移植患者个性化美法仑给药的努力。
