用强效口服β-分泌酶（BACE）抑制剂JNJ-54861911治疗后，分析脑脊液（CSF）和血浆β-淀粉样蛋白（Aβ）减少的动态变化。

Profiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ-54861911, a potent oral BACE inhibitor.

作者信息

Timmers Maarten, Van Broeck Bianca, Ramael Steven, Slemmon John, De Waepenaert Katja, Russu Alberto, Bogert Jennifer, Stieltjes Hans, Shaw Leslie M, Engelborghs Sebastiaan, Moechars Dieder, Mercken Marc, Liu Enchi, Sinha Vikash, Kemp John, Van Nueten Luc, Tritsmans Luc, Streffer Johannes Rolf

机构信息

Janssen Research and Development, Janssen Pharmaceutica N.V., Beerse, Belgium.

Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

出版信息

Alzheimers Dement (N Y). 2016 Aug 24;2(3):202-212. doi: 10.1016/j.trci.2016.08.001. eCollection 2016 Sep.

OBJECTIVES

Safety, tolerability, pharmacokinetics, and pharmacodynamics of a novel β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, JNJ-54861911, were assessed after single and multiple dosing in healthy participants.

METHODS

Two randomized, placebo-controlled, double-blind studies were performed using single and multiple ascending JNJ-54861911 doses (up to 14 days) in young and elderly healthy participants. Regular blood samples and frequent CSF samples, up to 36 hours after last dose, were collected to assess the pharmacokinetic and pharmacodynamic (Aβ, sAPPα,β,total levels) profiles of JNJ-54861911.

RESULTS

JNJ-54861911 was well-tolerated, adverse events were uncommon and unrelated to JNJ-54861911. JNJ-54861911 showed dose-proportional CSF and plasma pharmacokinetic profiles. Plasma- and CSF-Aβ and CSF-sAPPβ were reduced in a dose-dependent manner. Aβ reductions (up to 95%) outlasted exposure to JNJ-54861911. ε4 carrier status and baseline Aβ levels did not influence Aβ/sAPPβ reductions.

CONCLUSION

JNJ-54861911, a potent brain-penetrant BACE1 inhibitor, achieved high and stable Aβ reductions after single and multiple dosing in healthy participants.

目的

在健康受试者单次和多次给药后，评估新型β-分泌酶1（BACE1）抑制剂JNJ-54861911的安全性、耐受性、药代动力学和药效学。

方法

在年轻和老年健康受试者中进行了两项随机、安慰剂对照、双盲研究，使用单次和多次递增剂量的JNJ-54861911（最长14天）。在最后一剂给药后长达36小时内，定期采集血样和频繁采集脑脊液样本，以评估JNJ-54861911的药代动力学和药效学（Aβ、sAPPα、β、总水平）特征。

结果

JNJ-54861911耐受性良好，不良事件罕见且与JNJ-54861911无关。JNJ-54861911显示出剂量成比例的脑脊液和血浆药代动力学特征。血浆和脑脊液中的Aβ以及脑脊液中的sAPPβ以剂量依赖性方式降低。Aβ的降低（高达95%）持续时间超过了JNJ-54861911的暴露时间。ε4携带者状态和基线Aβ水平不影响Aβ/sAPPβ的降低。