Anand Ravi, Seiberling Michael, Kamtchoua Thierry, Pokorny Rolf
Anand Pharma Consulting, Oberwil, Switzerland.
Clin Pharmacokinet. 2007;46(4):351-8. doi: 10.2165/00003088-200746040-00007.
The FG loop peptide (FGL(L)), a novel mimetic of the neural cell adhesion molecule (NCAM), is in clinical development for neurodegenerative disorders such as Alzheimer's disease. Preclinical studies in rats, dogs and monkeys have demonstrated exposure in plasma and cerebrospinal fluid after parenteral or intranasal administration of FGL(L), with no systemic toxicity. This article reports on the results of the first administration of FGL(L) in humans.
To determine the tolerability, safety and pharmacokinetics of ascending, single intranasal doses of FGL(L) 25, 100 and 200mg in healthy subjects.
In an 8-day, open-label, phase I study, 24 healthy male volunteers (mean age 42 [range 24-55] years) received single intranasal doses of FGL(L) (25, 100 and 200mg) in accordance with an ascending dose, sequential-cohort design.
All three intranasal doses of FGL(L) were well tolerated and there were no clinical notable abnormalities in ECG recordings, vital signs or laboratory tests. Three subjects (13%) reported five adverse events. A transient (<3 minutes) burning sensation in the nose was reported in two subjects at the 200mg dose level while runny eyes (<2 minutes) were experienced in one subject at 25mg. These events had an onset immediately following intranasal administration, and a relationship to FGL(L) was suspected. One of the latter subjects who had experienced a burning sensation in the nose also experienced dizziness, vomiting and headache with onset >2 days after single-dose administration of FGL(L); no relationship to the study drug was suspected. Quantifiable plasma concentrations of FGL(L) were observed up to 1 hour after intranasal administration of the 100mg dose and up to 4 hours after the 200mg dose (plasma FGL(L) concentrations were undetectable at all timepoints for the 25mg dose). Increasing doses of FGL(L) were associated with higher systemic exposures: mean C(max) 0.52 ng/mL and 1.38 ng/mL (100mg and 200mg, respectively); mean AUC(24) 1.27 ng x h/mL and 4.05 ng x h/mL (100mg and 200mg, respectively).
Intranasal administration of FGL(L) (25, 100 and 200mg) was well tolerated in healthy male volunteers, with no safety concerns and a pharmacokinetic profile that was generally dose related. Further studies are currently being planned to evaluate the effects of FGL(L) in patients with Alzheimer's disease.
FG环肽（FGL(L)）是神经细胞黏附分子（NCAM）的一种新型模拟物，正在针对阿尔茨海默病等神经退行性疾病进行临床开发。在大鼠、狗和猴子身上进行的临床前研究表明，经肠胃外或鼻内给药FGL(L)后，其在血浆和脑脊液中均有暴露，且无全身毒性。本文报告了FGL(L)首次在人体给药的结果。
确定健康受试者单次鼻内递增剂量25、100和200mg FGL(L)的耐受性、安全性和药代动力学。
在一项为期8天的开放标签I期研究中，24名健康男性志愿者（平均年龄42岁[范围24 - 55岁]）按照递增剂量、序贯队列设计接受单次鼻内剂量的FGL(L)（25、100和200mg）。
FGL(L)的所有三种鼻内剂量耐受性良好，心电图记录、生命体征或实验室检查均无临床显著异常。三名受试者（13%）报告了5起不良事件。在200mg剂量水平，两名受试者报告有短暂（<3分钟）的鼻部烧灼感，而在25mg剂量时，一名受试者出现流泪（<2分钟）。这些事件在鼻内给药后立即出现，怀疑与FGL(L)有关。后者中一名曾有鼻部烧灼感的受试者在单次给药FGL(L) >2天后还出现头晕、呕吐和头痛；怀疑与研究药物无关。鼻内给予100mg剂量后1小时内以及200mg剂量后4小时内可观察到可量化的FGL(L)血浆浓度（25mg剂量在所有时间点血浆FGL(L)浓度均未检测到）。FGL(L)剂量增加与更高的全身暴露相关：平均C(max)分别为0.52 ng/mL和1.38 ng/mL（分别为100mg和200mg）；平均AUC(24)分别为1.27 ng·h/mL和4.05 ng·h/mL（分别为100mg和200mg）。
健康男性志愿者鼻内给予FGL(L)（25、100和200mg）耐受性良好，无安全问题，药代动力学特征一般与剂量相关。目前正在计划进一步研究以评估FGL(L)对阿尔茨海默病患者的影响。
