Safety, tolerability, pharmacokinetics, and Aβ levels after short-term administration of R-flurbiprofen in healthy elderly individuals
Safety, tolerability, pharmacokinetics, and Aβ levels after short-term administration of R-flurbiprofen in healthy elderly individuals
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DOI：
10.1097/wad.0b013e31815d1048
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发表时间：
2007-10-01
影响因子：
2.1
通讯作者：
Koo, Edward H.
中科院分区：
文献类型：
--
作者：
Galasko, Douglas R.;Graff-Radford, Neil;Koo, Edward H.
为了评估R-氟比洛芬（Tarenflurbil）在正常老年人中的安全性、耐受性和药代动力学特性，并确定药物对淀粉样蛋白β 42（A β 42）水平的影响，我们对48名55至80岁的健康受试者进行了一项双盲、安慰剂对照研究。三个连续的队列被随机分配至400、800或1600 mg/d剂量组或安慰剂组，分2次给药，持续21天。采集血液和脑脊液用于药代动力学研究，并测量基线和第21天的A β水平。R-氟比洛芬在所有3个剂量下均耐受良好。该化合物以剂量依赖性方式穿透血脑屏障。从基线至第21天，研究组之间的比较显示脑脊液A β 42水平的变化无显著差异，治疗第21天药物谷浓度时血浆A β 42水平的变化无显著差异。对血浆样本的药物浓度-效应的进一步分析显示，在血浆峰浓度时，较高的血浆药物浓度与较低的A β 42血浆水平相关（P = 0.016）。R-氟比洛芬具有良好的安全性，并显示出剂量依赖性的中枢神经系统渗透。血浆A β和药物峰值水平的探索性分析表明，血浆中存在短期效应，需要进行独立验证。这些老年人中R-氟比洛芬的安全性、耐受性和药代动力学特征支持了该化合物在阿尔茨海默病患者中的正在进行的研究。
To evaluate the safety and tolerability and pharmacokinetic properties of R-flurbiprofen (Tarenflurbil) in normal elderly individuals and to determine the effect of the drug on amyloid beta 42 (A beta 42) levels, we conducted a double-blind, placebo-controlled study of 48 healthy subjects aged 55 to 80. Three successive cohorts were randomized to doses of 400, 800, or 1600mg/d, or placebo, given as 2 divided doses for 21 days. Blood and cerebrospinal fluid were collected for pharmacokinetic studies and measurement of A beta levels at baseline and on day 21. R-flurbiprofen was well-tolerated at all 3 doses. The compound penetrated the blood-brain barrier in a dose-dependent manner. From baseline to 21 days, comparisons between study groups revealed no significant differences in changes of cerebrospinal fluid A beta 42 levels and no significant differences in changes of plasma A beta 42 levels at the time of trough drug level at 21 days of treatment. Further analysis of drug concentration-response for plasma samples showed that at the time of peak plasma concentration, higher plasma drug concentration was related to lower A beta 42 plasma levels (P = 0.016). R-flurbiprofen had an excellent safety profile and showed dose-dependent central nervous system penetration. Exploratory analyses of plasma A beta and peak drug levels suggested a short-term effect in plasma that warrants independent verification. The safety, tolerability, and pharmacokinetic profile of R-flurbiprofen in these older individuals support the ongoing studies of this compound in patients with Alzheimer disease.