Skip to main content
SpringerLink
Log in

Model-based meta-analysis of the effects of non-selective and α1-selective GABAA receptor agonists in healthy volunteers

  • Pharmacodynamics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Rudolph U, Knoflach F (2011) Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat Rev Drug Discov 10(9):685–697

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Dell’Osso B, Lader M (2013) Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? A critical reappraisal. Eur Psychiatry 28(1):7–20

    Article  PubMed  Google Scholar 

  3. McKernan RM, Rosahl TW, Reynolds DS et al (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nat Neurosci 3(6):587–592

    Article  CAS  PubMed  Google Scholar 

  4. Rudolph U, Crestani F, Benke D et al (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401(6755):796–800

    Article  CAS  PubMed  Google Scholar 

  5. Low K, Crestani F, Keist R et al (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290(5489):131–134

    Article  CAS  PubMed  Google Scholar 

  6. Rudolph U, Crestani F, Mohler H (2001) GABA(A) receptor subtypes: dissecting their pharmacological functions. Trends Pharmacol Sci 22(4):188–194

    Article  CAS  PubMed  Google Scholar 

  7. Morris HV, Dawson GR, Reynolds DS et al (2006) Both alpha2 and alpha3 GABAA receptor subtypes mediate the anxiolytic properties of benzodiazepine site ligands in the conditioned emotional response paradigm. Eur J Neurosci 23(9):2495–2504

    Article  CAS  PubMed  Google Scholar 

  8. Dias R, Sheppard WF, Fradley RL et al (2005) Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines. J Neurosci 25(46):10682–10688

    Article  CAS  PubMed  Google Scholar 

  9. Atack JR, Hutson PH, Collinson N et al (2005) Anxiogenic properties of an inverse agonist selective for alpha3 subunit-containing GABA a receptors. Br J Pharmacol 144(3):357–366

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Crestani F, Keist R, Fritschy JM et al (2002) Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc Natl Acad Sci U S A 99(13):8980–8985

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Collinson N, Kuenzi FM, Jarolimek W et al (2002) Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci 22(13):5572–5580

    CAS  PubMed  Google Scholar 

  12. Atack JR (2011) GABAA receptor subtype-selective modulators. II. Alpha5-selective inverse agonists for cognition enhancement. Curr Top Med Chem 11(9):1203–1214

    Article  CAS  PubMed  Google Scholar 

  13. Mohler H, Crestani F, Rudolph U (2001) GABA(A)-receptor subtypes: a new pharmacology. Curr Opin Pharmacol 1(1):22–25

    Article  CAS  PubMed  Google Scholar 

  14. O’Brien CP (2005) Benzodiazepine use, abuse, and dependence. J Clin Psychiatry 66 Suppl 2(6):28–33

    Google Scholar 

  15. Dämgen K, Lüddens H (1999) Zaleplon displays a selectivity to recombinant GABAA receptors different from zolipdem, zopiclone and benzodiazepines. Neurosci Res Commun 25(3):139–148

    Article  Google Scholar 

  16. Petroski RE, Pomeroy JE, Das R et al (2006) Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors. J Pharmacol Exp Ther 317(1):369–377

    Article  CAS  PubMed  Google Scholar 

  17. Montplaisir J, Hawa R, Moller H et al (2003) Zopiclone and zaleplon vs benzodiazepines in the treatment of insomnia: Canadian consensus statement. Hum Psychopharmacol 18(1):29–38

    Article  CAS  PubMed  Google Scholar 

  18. Israel AG, Kramer JA (2002) Safety of zaleplon in the treatment of insomnia. Ann Pharmacother 36(5):852–859

    Article  CAS  PubMed  Google Scholar 

  19. de Haas SL, de Visser SJ, van der Post JP et al (2007) Pharmacodynamic and pharmacokinetic effects of TPA023, a GABA(A) alpha(2,3) subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers. J Psychopharmacol 21(4):374–383

    Article  PubMed  Google Scholar 

  20. de Haas SL, de Visser SJ, van der Post JP et al (2008) Pharmacodynamic and pharmacokinetic effects of MK-0343, a GABA(A) alpha2,3 subtype selective agonist, compared to lorazepam and placebo in healthy male volunteers. J Psychopharmacol 22(1):24–32

    Article  PubMed  Google Scholar 

  21. de Haas SL, Franson KL, Schmitt JA et al (2009) The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A alpha2,3 selective agonist, in comparison with lorazepam in healthy volunteers. J Psychopharmacol 23(6):625–632

    Article  PubMed  Google Scholar 

  22. Atack JR, Hallett DJ, Tye S et al (2011) Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist. J Psychopharmacol 25(3):329–344

    Article  CAS  PubMed  Google Scholar 

  23. Rudolph U, Mohler H (2006) GABA-based therapeutic approaches: GABAA receptor subtype functions. Curr Opin Pharmacol 6(1):18–23

    Article  CAS  PubMed  Google Scholar 

  24. Vinkers CH, Olivier B (2012) Mechanisms underlying tolerance after long-term benzodiazepine use: a future for subtype-selective GABA(A) receptor modulators? Adv Pharmacol Sci 2012:416864

    PubMed Central  PubMed  Google Scholar 

  25. de Visser SJ, van der Post JP, de Waal PP et al (2003) Biomarkers for the effects of benzodiazepines in healthy volunteers. Br J Clin Pharmacol 55(1):39–50

    Article  PubMed Central  PubMed  Google Scholar 

  26. Chen X, de Haas S, de Kam M et al (2012) An overview of the CNS-Pharmacodynamic profiles of nonselective and selective GABA agonists. Adv Pharmacol Sci 2012:134523

    PubMed Central  PubMed  Google Scholar 

  27. de Haas SL, Schoemaker RC, van Gerven JM et al (2010) Pharmacokinetics, pharmacodynamics and the pharmacokinetic/pharmacodynamic relationship of zolpidem in healthy subjects. J Psychopharmacol 24(11):1619–1629

    Article  PubMed  Google Scholar 

  28. Gupta SK, Ellinwood EH, Nikaido AM et al (1990) Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of benzodiazepines. I: Lorazepam. J Pharmacokinet Biopharm 18(2):89–102

    Article  CAS  PubMed  Google Scholar 

  29. Venkatakrishnan K, Culm KE, Ehrenberg BL et al (2005) Kinetics and dynamics of intravenous adinazolam, N-desmethyl adinazolam, and alprazolam in healthy volunteers. J Clin Pharmacol 45(5):529–537

    Article  CAS  PubMed  Google Scholar 

  30. Mould DR, DeFeo TM, Reele S et al (1995) Simultaneous modeling of the pharmacokinetics and pharmacodynamics of midazolam and diazepam. Clin Pharmacol Ther 58(1):35–43

    Article  CAS  PubMed  Google Scholar 

  31. van Steveninck AL, Schoemaker HC, Pieters MS et al (1991) A comparison of the sensitivities of adaptive tracking, eye movement analysis and visual analog lines to the effects of incremental doses of temazepam in healthy volunteers. Clin Pharmacol Ther 50(2):172–180

    Article  PubMed  Google Scholar 

  32. Kamal MA, Smith DE, Cook J et al (2010) Pharmacodynamic differentiation of lorazepam sleepiness and dizziness using an ordered categorical measure. J Pharm Sci 99(8):3628–3641

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Garcia-Gea C, Ballester MR, Martinez J et al (2010) Rupatadine does not potentiate the CNS depressant effects of lorazepam: randomized, double-blind, crossover, repeated dose, placebo-controlled study. Br J Clin Pharmacol 69(6):663–674

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Farber RH, Burke PJ (2008) Post-bedtime dosing with indiplon in adults and the elderly: results from two placebo-controlled, active comparator crossover studies in healthy volunteers. Curr Med Res Opin 24(3):837–846

    Article  CAS  PubMed  Google Scholar 

  35. Lucchesi LM, Braga NI, Manzano GM et al (2005) Acute neurophysiological effects of the hypnotic zolpidem in healthy volunteers. Prog Neuropsychopharmacol Biol Psychiatry 29(4):557–564

    Article  CAS  PubMed  Google Scholar 

  36. Hou RH, Scaife J, Freeman C et al (2006) Relationship between sedation and pupillary function: comparison of diazepam and diphenhydramine. Br J Clin Pharmacol 61(6):752–760

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Hoever P, de Haas S, Winkler J et al (2010) Orexin receptor antagonism, a new sleep-promoting paradigm: an ascending single-dose study with almorexant. Clin Pharmacol Ther 87(5):593–600

    Article  CAS  PubMed  Google Scholar 

  38. Dixon R, Hughes AM, Nairn K et al (1998) Effects of the antimigraine compound zolmitriptan (‘Zomig’) on psychomotor performance alone and in combination with diazepam in healthy volunteers. Cephalalgia 18(7):468–475

    Article  CAS  PubMed  Google Scholar 

  39. Hege SG, Ellinwood EJ, Wilson WH et al (1997) Psychomotor effects of the anxiolytic abecarnil: a comparison with lorazepam. Psychopharmacology (Berl) 131(2):101–107

    Article  CAS  Google Scholar 

  40. Vermeeren A, Jackson JL, Muntjewerff ND et al (1995) Comparison of acute alprazolam (0.25, 0.50 and 1.0 mg) effects versus those of lorazepam 2 mg and placebo on memory in healthy volunteers using laboratory and telephone tests. Psychopharmacology (Berl) 118(1):1–9

    Article  CAS  Google Scholar 

  41. Gomeni R, Merlo-Pich E (2007) Bayesian modelling and ROC analysis to predict placebo responders using clinical score measured in the initial weeks of treatment in depression trials. Br J Clin Pharmacol 63(5):595–613

    Article  PubMed Central  PubMed  Google Scholar 

  42. Goyal N, Gomeni R (2013) A latent variable approach in simultaneous modeling of longitudinal and dropout data in schizophrenia trials. Eur Neuropsychopharmacol 23(11):1570–1576

    Article  CAS  PubMed  Google Scholar 

  43. Nucci G, Gomeni R, Poggesi I (2009) Model-based approaches to increase efficiency of drug development in schizophrenia: a can’t miss opportunity. Expert Opin Drug Discov 4(8):837–856

    Article  CAS  PubMed  Google Scholar 

  44. Beal SL, Sheiner LB, Boeckmann AJ. NONMEM User’s Guide – Part I–VII. Ellicott City, MD: Icon Development Solutions. ed.: 1989–2006.

  45. Keizer RJ, van Benten M, Beijnen JH et al (2011) Pirana and PCluster: a modeling environment and cluster infrastructure for NONMEM. Comput Methods Programs Biomed 101(1):72–79

    Article  PubMed  Google Scholar 

  46. Lindbom L, Ribbing J, Jonsson EN (2004) Perl-speaks-NONMEM (PsN)—a Perl module for NONMEM related programming. Comput Methods Programs Biomed 75(2):85–94

    Article  PubMed  Google Scholar 

  47. Sieghart W (1995) Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes. Pharmacol Rev 47(2):181–234

    CAS  PubMed  Google Scholar 

  48. Pritchett DB, Luddens H, Seeburg PH (1989) Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. Science 245(4924):1389–1392

    Article  CAS  PubMed  Google Scholar 

  49. Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47(3):211–218

    Article  Google Scholar 

  50. Zuo XC, Zhang BK, Jia SJ et al (2010) Effects of Ginkgo biloba extracts on diazepam metabolism: a pharmacokinetic study in healthy Chinese male subjects. Eur J Clin Pharmacol 66(5):503–509

    Article  PubMed  Google Scholar 

  51. Barbanoj MJ, Urbano G, Antonijoan R et al (2007) Different acute tolerance development to EEG, psychomotor performance and subjective assessment effects after two intermittent oral doses of alprazolam in healthy volunteers. Neuropsychobiology 55(3–4):203–212

    Article  CAS  PubMed  Google Scholar 

  52. Tornio A, Neuvonen PJ, Backman JT (2006) The CYP2C8 inhibitor gemfibrozil does not increase the plasma concentrations of zopiclone. Eur J Clin Pharmacol 62(8):645–651

    Article  CAS  PubMed  Google Scholar 

  53. Carlson JN, Haskew R, Wacker J et al (2001) Sedative and anxiolytic effects of zopiclone’s enantiomers and metabolite. Eur J Pharmacol 415(2–3):181–189

    Article  CAS  PubMed  Google Scholar 

  54. Saari TI, Laine K, Bertilsson L et al (2007) Voriconazole and fluconazole increase the exposure to oral diazepam. Eur J Clin Pharmacol 63(10):941–949

    Article  CAS  PubMed  Google Scholar 

  55. Hall J, Naranjo CA, Sproule BA et al (2003) Pharmacokinetic and pharmacodynamic evaluation of the inhibition of alprazolam by citalopram and fluoxetine. J Clin Psychopharmacol 23(4):349–357

    Article  CAS  PubMed  Google Scholar 

  56. Caille G, du Souich P, Spenard J et al (1984) Pharmacokinetic and clinical parameters of zopiclone and trimipramine when administered simultaneously to volunteers. Biopharm Drug Dispos 5(2):117–125

    Article  CAS  PubMed  Google Scholar 

  57. Smith AJ, Alder L, Silk J et al (2001) Effect of alpha subunit on allosteric modulation of ion channel function in stably expressed human recombinant gamma-aminobutyric acid(A) receptors determined using (36)Cl ion flux. Mol Pharmacol 59(5):1108–1118

    CAS  PubMed  Google Scholar 

  58. Patat A, Perault MC, Vandel B et al (1995) Assessment of the interaction between a partial agonist and a full agonist of benzodiazepine receptors, based on psychomotor performance and memory, in healthy volunteers. J Psychopharmacol 9(2):91–101

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge support from Dr. Guangli Ma [Pfizer (China) Research and Development Center]. This work was sponsored by Pfizer Inc.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. The State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China

    Yu-Peng Ren, Liang Li, Tian-Yan Zhou & Wei Lu

  2. Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Yu-Peng Ren, Liang Li, Tian-Yan Zhou & Wei Lu

  3. Pfizer (China) Research and Development Center, Shanghai, 201203, China

    Ru-Jia Xie

  4. Pfizer Inc, Sandwich, UK

    Scott Marshall

  5. Center of Schizophrenia, Beijing Institute for Brain Disorders, Laboratory of Brain Disorders (Capital Medical University), Ministry of Science and Technology, Beijing, 100088, China

    Wei Lu

Authors
  1. Yu-Peng Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ru-Jia Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Scott Marshall
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tian-Yan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei Lu.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 1324 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ren, YP., Xie, RJ., Marshall, S. et al. Model-based meta-analysis of the effects of non-selective and α1-selective GABAA receptor agonists in healthy volunteers. Eur J Clin Pharmacol 71, 1209–1221 (2015). https://doi.org/10.1007/s00228-015-1918-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-015-1918-8

Keywords

Search

Navigation