Burstein Aaron H, Zhao Qinying, Ross Joel, Styren Scot, Landen Jaren W, Ma Wendy W, McCush Fred, Alvey Christine, Kupiec James W, Bednar Martin M
Neuroscience Research Unit, Pfizer Inc, Groton, CT 06340, USA.
Clin Neuropharmacol. 2013 Jan-Feb;36(1):8-13. doi: 10.1097/WNF.0b013e318279bcfa.
Ponezumab (PF-04360365) is a humanized anti-amyloid beta (Aβ) monoclonal antibody designed for treatment of Alzheimer disease (AD). A single 2-hour intravenous infusion of 0.1 to 10 mg/kg was previously shown to be safe and well tolerated in subjects with mild to moderate AD, with measurable effects on plasma and cerebrospinal fluid Aβ. This phase I, dose-escalation, open-label study evaluated the safety, pharmacokinetics, and pharmacodynamics of a single 10-minute intravenous infusion.
Subjects with mild to moderate AD received ponezumab 1 mg/kg (n = 3), 3 mg/kg (n = 3), 5 mg/kg (n = 4), or 10 mg/kg (n = 5). They were followed up as outpatients for 6 months.
All subjects completed the trial. Ponezumab was safe and well tolerated with no deaths, withdrawals, or drug-related moderate, severe, or serious adverse events. Mild drug-related adverse events included headache (3 patients) and lethargy and hypoesthesia (both in 1 patient). No infusion reactions, clinically meaningful laboratory abnormalities, vital sign changes, electrocardiographic changes, or antidrug antibodies were detected. There was no evidence of brain microhemorrhage, vasogenic edema, encephalitis, or other imaging abnormality. Cognitive function showed no treatment-related trends. Ponezumab displayed approximately dose-proportional increases in plasma exposure. Steady-state volume of distribution was 113 to 172 mL/kg, clearance was 2.7 to 3.0 mL/d/kg, and terminal half-life was 35 to 52 days. Plasma maximum observed concentration and the area under the plasma concentration-time profile from time 0 extrapolated to infinite time of Aβ(1-x) and Aβ(1-40) increased dose-dependently.
Administration of ponezumab as a 10-minute infusion was safe and well tolerated and produced effects on plasma Aβ species comparable with a 2-hour infusion. Shorter infusions may provide more flexibility, comfort, and convenience for patients and caregivers.
泊奈单抗（PF-04360365）是一种人源化抗淀粉样β蛋白（Aβ）单克隆抗体，设计用于治疗阿尔茨海默病（AD）。先前研究表明，对轻至中度AD患者进行单次2小时静脉输注0.1至10mg/kg剂量的泊奈单抗是安全且耐受性良好的，对血浆和脑脊液中的Aβ有可测量的影响。这项I期剂量递增开放标签研究评估了单次10分钟静脉输注的安全性、药代动力学和药效学。
轻至中度AD患者接受1mg/kg（n = 3）、3mg/kg（n = 3）、5mg/kg（n = 4）或10mg/kg（n = 5）剂量的泊奈单抗治疗。他们作为门诊患者接受了6个月的随访。
所有受试者均完成试验。泊奈单抗安全且耐受性良好，无死亡、退出试验或与药物相关的中度、重度或严重不良事件。轻度药物相关不良事件包括头痛（3例患者）、嗜睡和感觉减退（各1例患者）。未检测到输液反应、具有临床意义的实验室异常、生命体征变化、心电图变化或抗药物抗体。没有脑微出血、血管源性水肿、脑炎或其他影像学异常的证据。认知功能未显示出与治疗相关的趋势。泊奈单抗的血浆暴露量呈现出近似剂量比例的增加。稳态分布容积为113至172mL/kg，清除率为2.7至3.0mL/（d·kg），终末半衰期为35至52天。血浆中观察到的最大浓度以及从时间0外推至无限时间的Aβ（1-x）和Aβ（1-40）血浆浓度-时间曲线下面积呈剂量依赖性增加。
以10分钟输注方式给药的泊奈单抗安全且耐受性良好，对血浆Aβ种类产生的影响与2小时输注相当。更短的输注时间可能会为患者和护理人员提供更大的灵活性、舒适度和便利性。
