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学科主题: 药学
题名:
Model-based meta-analysis of the effects of non-selective and alpha(1)-selective GABA(A) receptor agonists in healthy volunteers
作者: Ren, Yu-Peng1,2; Xie, Ru-Jia3; Marshall, Scott4; Li, Liang1,2; Zhou, Tian-Yan1,2; Lu, Wei1,2,5
关键词: Model-based meta-analysis ; NONMEM ; PK/PD ; Adverse events ; GABA(A) receptor ; Benzodiazepines
刊名: EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY
发表日期: 2015-10-01
DOI: 10.1007/s00228-015-1918-8
卷: 71, 期:10, 页:1209-1221
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Pharmacology & Pharmacy
研究领域[WOS]: Pharmacology & Pharmacy
关键词[WOS]: SUBTYPE-SELECTIVE AGONIST ; PSYCHOMOTOR PERFORMANCE ; BENZODIAZEPINE RECEPTORS ; ANXIOLYTIC PROPERTIES ; LORAZEPAM ; PLACEBO ; ALPRAZOLAM ; ZOPICLONE ; DIAZEPAM ; SUBUNIT
英文摘要:

Purpose To quantify pharmacokinetic (PK) and pharmacodynamic (PD) relationships of various classes of GABA(A) agonists in healthy volunteers, in order to investigate the sensitivity of the biomarker responses due to differing GABA(A)-subtype selectivity and to explore the correlation between biomarker responses and side effects of these drugs.

Methods A comprehensive search was conducted for published placebo-controlled clinical studies of non- and alpha(1)-selective GABA(A) drugs in healthy volunteers. PK/PD models were developed for concentrations and biomarker outcomes (saccadic eye movement (SEM), visual analogue scale (VAS), digit symbol substitution task (DSST), and critical flicker fusion test (CFFT)) extracted from included studies. Predicted responses and equivalent doses for biomarkers (based on predicted response) were used to compare drug effects. And the relationship between biomarkers and safety was explored by linear regression.

Results A total of 2237 data from 163 articles were included. Based on PK and placebo effect modeling, linear biomarker-concentration relationships well fit the data. The alpha(1)-selective compounds had similar equivalent doses for VAS, DSST, and CFFT (4.7-6.7 mg), which were about three to seven times lower than that for SEM (14.4-35.5 mg), while such difference was less evident for non-selective drugs. DSST had the highest correlations with incidences of somnolence and dizziness.

Conclusions The integral PK/PD models of GABA(A) agonists were established in healthy volunteers. SEM was identified as the most sensitive biomarker in differentiating GABA(A) receptor alpha(1) subtype selective compounds. The exploratory analysis implied that different relationships existed between the drug effects on biomarkers and the adverse event profiles in healthy volunteers.

语种: 英语
项目资助者: Pfizer Inc.
WOS记录号: WOS:000360996300006
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/59962
Appears in Collections:北京大学药学院_药剂学系_期刊论文

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作者单位: 1.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
2.Pfizer China Res & Dev Ctr, Shanghai 201203, Peoples R China
3.Pfizer Inc, Sandwich, Kent, England
4.Peking Univ, Hlth Sci Ctr, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China
5.Capital Med Univ, Ctr Schizophrenia, Beijing Inst Brain Disorders, Lab Brain Disorders,Minist Sci & Technol, Beijing 100088, Peoples R China

Recommended Citation:
Ren, Yu-Peng,Xie, Ru-Jia,Marshall, Scott,et al. Model-based meta-analysis of the effects of non-selective and alpha(1)-selective GABA(A) receptor agonists in healthy volunteers[J]. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY,2015,71(10):1209-1221.
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