Haroldsen Peter E, Sisic Zlatko, Datt Joe, Musson Donald G, Ingenito Gary
BioMarin Pharmaceutical Inc, Novato, California, USA.
BioMarin Europe Ltd, London, United Kingdom.
Clin Ther. 2017 Jul;39(7):1360-1370. doi: 10.1016/j.clinthera.2017.05.353. Epub 2017 Jun 19.
The purpose of this study is to evaluate safety, tolerability, and pharmacokinetic (PK) properties of amifampridine phosphate (Firdapse™) and its major inactive 3-N-acetyl metabolite in renally impaired and healthy individuals with slow acetylator (SA) and rapid acetylator (RA) phenotypes.
This was a Phase I, multicenter, open-label study of the PK properties and safety profile of amifampridine phosphate in individuals with normal, mild, moderate, or severely impaired renal function. Amifampridine phosphate was given as a single 10 mg (base equivalent) dose, and the plasma and urine PK properties of amifampridine and its 3-N-acetyl metabolite were determined. The safety profile was evaluated by monitoring adverse events (AEs), clinical laboratory tests, and physical examinations.
Amifampridine clearance was predominantly metabolic through N-acetylation, regardless of renal function in both acetylator phenotypes. In individuals with normal renal function, mean renal clearance represented approximately 3% and 18% of the total clearance of amifampridine in RA and SA, respectively. Large differences in amifampridine exposure were observed between acetylation phenotypes across renal function levels. Mean amifampridine exposure values of AUC and C were up to 8.8-fold higher in the SA group compared with the RA group across renal function levels. By comparison, mean AUC was less affected by renal function within an acetylator group, only 2- to 3-fold higher in individuals with severe renal impairment (RI) compared with those with normal renal function. Exposure to amifampridine in the SA group with normal renal function was higher (AUC approximately 1.8-fold; C approximately 4.1-fold) than the RA group with severe RI. Exposure to the inactive 3-N-acetyl metabolite was higher than amifampridine in both acetylator groups, independent of renal function level. The metabolite is cleared by renal excretion, and exposure was clearly dependent on renal function with 4.0- to 6.8-fold increases in AUC from normal to severe RI. No new tolerability findings were observed.
A single dose of 10 mg of amifampridine phosphate was well tolerated, independent of renal function and acetylator status. The results indicate that the PK profile of amifampridine is affected by metabolic acetylator phenotype to a greater extent than by renal function level, supporting Firdapse™ administration in individuals with RI in line with current labeling recommendations. Amifampridine should be dosed to effect per the individual patient need, altering administration frequency and dose in normal through severe RI. The therapeutic dose of amifampridine phosphate should be tailored to the individual patient needs by gradual dose titration up to the present maximum recommended dose (60-80 mg/day) or until dose-limiting AEs intervene to avoid overdosing and underdosing. EudraCT identifier: 2013-005349-35.
本研究旨在评估磷酸阿米芬啶（Firdapse™）及其主要无活性的3-N-乙酰代谢物在肾功能受损以及具有慢乙酰化表型（SA）和快乙酰化表型（RA）的健康个体中的安全性、耐受性和药代动力学（PK）特性。
这是一项关于磷酸阿米芬啶在肾功能正常、轻度、中度或重度受损个体中的PK特性和安全性的I期多中心开放标签研究。给予磷酸阿米芬啶单次10mg（碱基当量）剂量，并测定阿米芬啶及其3-N-乙酰代谢物的血浆和尿液PK特性。通过监测不良事件（AE）、临床实验室检查和体格检查来评估安全性。
无论乙酰化表型如何，阿米芬啶的清除主要通过N-乙酰化代谢，不受肾功能影响。在肾功能正常的个体中，平均肾清除率在RA和SA中分别约占阿米芬啶总清除率的3%和18%。在不同肾功能水平的乙酰化表型之间观察到阿米芬啶暴露存在较大差异。在所有肾功能水平上，SA组的阿米芬啶AUC和C的平均暴露值比RA组高8.8倍。相比之下，在乙酰化表型组内，肾功能对AUC的影响较小，与肾功能正常的个体相比，重度肾功能损害（RI）个体的AUC仅高2至3倍。肾功能正常的SA组中阿米芬啶暴露高于重度RI的RA组（AUC约高1.8倍；C约高4.1倍）。在两个乙酰化表型组中，无活性的3-N-乙酰代谢物的暴露均高于阿米芬啶，且与肾功能水平无关。该代谢物通过肾脏排泄清除，其暴露明显依赖于肾功能，从正常到重度RI，AUC增加4.0至6.8倍。未观察到新的耐受性发现。
单次给予10mg磷酸阿米芬啶耐受性良好，与肾功能和乙酰化状态无关。结果表明，阿米芬啶的PK特征受代谢乙酰化表型的影响程度大于肾功能水平，支持按照当前标签建议在RI个体中使用Firdapse™。应根据个体患者需求调整阿米芬啶剂量，在肾功能从正常到重度受损时改变给药频率和剂量。磷酸阿米芬啶的治疗剂量应根据个体患者需求进行调整，通过逐渐滴定剂量至目前最大推荐剂量（60 - 80mg/天），或直到出现剂量限制性AE以避免用药过量和用药不足。欧盟临床试验数据库标识符：2013 - 005349 - 35。
