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Model-based meta-analysis of the effects of non-selective and alpha(1)-selective GABA(A) receptor agonists in healthy volunteers
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
2015-10-01
DOI10.1007/s00228-015-1918-8
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
WOS记录号WOS:000360996300006
通讯作者邮箱luwei_pk@bjmu.edu.cn
资助机构Pfizer Inc.
引用统计
被引频次:3[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
版本出版稿
条目标识符http://ir.bjmu.edu.cn/handle/400002259/59962
专题北京大学药学院_药剂学系
作者单位1.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
2.Peking Univ, Hlth Sci Ctr, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China
3.Pfizer China Res & Dev Ctr, Shanghai 201203, Peoples R China
4.Pfizer Inc, Sandwich, Kent, England
5.Capital Med Univ, Ctr Schizophrenia, Beijing Inst Brain Disorders, Lab Brain Disorders,Minist Sci & Technol, Beijing 100088, Peoples R China
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GB/T 7714
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.
APA Ren, Yu-Peng,Xie, Ru-Jia,Marshall, Scott,Li, Liang,Zhou, Tian-Yan,&Lu, Wei.(2015).Model-based meta-analysis of the effects of non-selective and alpha(1)-selective GABA(A) receptor agonists in healthy volunteers.EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY,71(10),1209-1221.
MLA Ren, Yu-Peng,et al."Model-based meta-analysis of the effects of non-selective and alpha(1)-selective GABA(A) receptor agonists in healthy volunteers".EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY 71.10(2015):1209-1221.
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