title: Model-based meta-analysis of the effects of non-selective and α1-selective GABAA receptor agonists in healthy volunteers.
abstract: OBJECTIVE
  To quantify pharmacokinetic (PK) and pharmacodynamic (PD) relationships of various classes of GABAA agonists in healthy volunteers, in order to investigate the sensitivity of the biomarker responses due to differing GABAA-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 α1-selective GABAA 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 α1-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 GABAA agonists were established in healthy volunteers. SEM was identified as the most sensitive biomarker in differentiating GABAA receptor α1 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.
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China.|Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Yu-Peng
authors.initials: YP
authors.lastname: Ren
authors.affiliation: Pfizer (China) Research and Development Center, Shanghai, 201203, China.
authors.forename: Ru-Jia
authors.initials: RJ
authors.lastname: Xie
authors.affiliation: Pfizer Inc, Sandwich, UK.
authors.forename: Scott
authors.initials: S
authors.lastname: Marshall
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China.|Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China.|Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Tian-Yan
authors.initials: TY
authors.lastname: Zhou
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China. luwei_pk@bjmu.edu.cn.|Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China. luwei_pk@bjmu.edu.cn.|Center of Schizophrenia, Beijing Institute for Brain Disorders, Laboratory of Brain Disorders (Capital Medical University), Ministry of Science and Technology, Beijing, 100088, China. luwei_pk@bjmu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
mesh_terms: D015415:Biomarkers; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D058785:GABA-A Receptor Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D064368:Healthy Volunteers; D006801:Humans; D011485:Protein Binding; D012438:Saccades; D064232:Visual Analog Scale
chemical_list: D015415:Biomarkers; D058785:GABA-A Receptor Agonists
keywords: Adverse events; Benzodiazepines; GABAA receptor; Model-based meta-analysis; NONMEM; PK/PD