Skip to main content
SpringerLink
Log in

Pharmacological Interactions between the Dual Orexin Receptor Antagonist Daridorexant and Ethanol in a Double-Blind, Randomized, Placebo-Controlled, Double-Dummy, Four-Way Crossover Phase I Study in Healthy Subjects

  • Original Research Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Background

Daridorexant (ACT-541468) is a potent dual orexin receptor antagonist under development for the treatment of sleep disorders. Concomitant intake of ethanol and hypnotics has been shown to result in additive/supra-additive depression of the central nervous system, resulting in pronounced sedation.

Objective

The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between ethanol and daridorexant.

Method

This was a single-center, double-blind, placebo-controlled, randomized, four-way crossover study conducted in 19 healthy male/female subjects. Subjects received the following four treatments: ethanol with daridorexant, daridorexant alone, ethanol alone, and placebo. Daridorexant 50 mg and the matching placebo were administered as single oral tablets. Ethanol was infused intravenously and clamped at a level of 0.6 g/L for 5 h. The PK of ethanol and daridorexant were assessed and a battery of PD tests performed.

Results

Concomitant administration of ethanol prolonged the time to reach maximum plasma concentrations (tmax) of daridorexant (median difference 1.25 h). No other relevant PK interactions were observed. Coadministration with ethanol produced a numerically greater impairment on saccadic peak velocity, body sway, visual analog scale (VAS) alertness, VAS alcohol intoxication, smooth pursuit, and adaptive tracking compared with daridorexant alone. All treatments were generally well tolerated without serious adverse events (AEs). The most commonly reported treatment-emergent AEs following coadministration of daridorexant and ethanol included somnolence, headache, fatigue, sudden onset of sleep, and dizziness.

Conclusions

Apart from a shift in tmax, no relevant changes in PK parameters were observed following coadministration of daridorexant and ethanol. The coadministration led to reinforced drug actions that were, at most, indicative of infra-additive effects on certain PD markers. Patients will be advised not to consume ethanol with daridorexant.

Clinical Trials Registration number:

NCT03609775 (ClinicalTrials.gov Identifier)

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

Similar content being viewed by others

References

  1. Treiber A, de Kanter R, Roch C, Gatfield J, Boss C, von Raumer M, et al. The use of physiology-based pharmacokinetic and pharmacodynamic modeling in the discovery of the dual orexin receptor antagonist ACT-541468. J Pharmacol Exp Ther. 2017;362(3):489–503.

    CAS  PubMed  Google Scholar 

  2. Muehlan C, Fischer H, Zimmer D, Aissaoui H, Grimont J, Boss C, et al. Metabolism of the dual orexin receptor antagonist ACT-541468, based on microtracer/accelerator mass spectrometry. Curr Drug Metab. 2019;20(4):254–65.

    CAS  PubMed  Google Scholar 

  3. Muehlan C, Heuberger J, Juif PE, Croft M, van Gerven J, Dingemanse J. Accelerated development of the dual orexin receptor antagonist ACT-541468: integration of a microtracer in a first-in-human study. Clin Pharmacol Ther. 2018;104(5):1022–9.

    CAS  PubMed  Google Scholar 

  4. Zenklusen I, Muehlan C, Ulc I, Liska J, Dingemanse J. The dual orexin receptor antagonist daridorexant does not affect the pharmacokinetics of the BCRP substrate rosuvastatin. Clin Exp Pharmacol Physiol. 2020. https://doi.org/10.1111/1440-1681.13370.

    Article  PubMed  Google Scholar 

  5. Boof ML, Alatrach A, Ufer M, Dingemanse J. Interaction potential of the dual orexin receptor antagonist ACT-541468 with CYP3A4 and food: results from two interaction studies. Eur J Clin Pharmacol. 2019;75(2):195–205.

    CAS  PubMed  Google Scholar 

  6. Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N, Muraki Y, et al. Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron. 2005;46(2):297–308.

    CAS  PubMed  Google Scholar 

  7. Tannenbaum PL, Tye SJ, Stevens J, Gotter AL, Fox SV, Savitz AT, et al. Inhibition of orexin signaling promotes sleep yet preserves salient arousability in monkeys. Sleep. 2016;39(3):603–12.

    PubMed  PubMed Central  Google Scholar 

  8. Otmani S, Demazieres A, Staner C, Jacob N, Nir T, Zisapel N, et al. Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Hum Psychopharmacol. 2008;23(8):693–705.

    CAS  PubMed  Google Scholar 

  9. Dauvilliers Y, Zammit G, Fietze I, Mayleben D, Seboek Kinter D, Pain S, et al. Daridorexant, a new dual orexin receptor antagonist to treat insomnia disorder. Ann Neurol. 2020;87(3):347–56.

    CAS  PubMed  Google Scholar 

  10. Zammit G, Dauvilliers Y, Pain S, Sebok Kinter D, Mansour Y, Kunz D. Daridorexant, a new dual orexin receptor antagonist, in elderly subjects with insomnia disorder. Neurology. 2020;94(21):e2222–32.

    CAS  PubMed  Google Scholar 

  11. Muehlan C, Boehler M, Brooks S, Zuiker R, van Gerven J, Dingemanse J. Clinical pharmacology of the dual orexin receptor antagonist ACT-541468 in elderly subjects: exploration of pharmacokinetics, pharmacodynamics and tolerability following single-dose morning and repeated-dose evening administration. J Psychopharmacol. 2020;34(3):326–35.

    PubMed  Google Scholar 

  12. Muehlan C, Brooks S, Zuiker R, van Gerven J, Dingemanse J. Multiple-dose clinical pharmacology of ACT-541468, a novel dual orexin receptor antagonist, following repeated-dose morning and evening administration. Eur Neuropsychopharmacol. 2019;29(7):847–57.

    CAS  PubMed  Google Scholar 

  13. Jang GR, Harris RZ. Drug interactions involving ethanol and alcoholic beverages. Expert Opin Drug Metab Toxicol. 2007;3(5):719–31.

    CAS  PubMed  Google Scholar 

  14. Zoethout RW, Delgado WL, Ippel AE, Dahan A, van Gerven JM. Functional biomarkers for the acute effects of alcohol on the central nervous system in healthy volunteers. Br J Clin Pharmacol. 2011;71(3):331–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hesse LM, von Moltke LL, Greenblatt DJ. Clinically important drug interactions with zopiclone, zolpidem and zaleplon. CNS Drugs. 2003;17(7):513–32.

    CAS  PubMed  Google Scholar 

  16. van Steveninck AL, Gieschke R, Schoemaker HC, Pieters MS, Kroon JM, Breimer DD, et al. Pharmacodynamic interactions of diazepam and intravenous alcohol at pseudo steady state. Psychopharmacology. 1993;110(4):471–8.

    PubMed  Google Scholar 

  17. van Steveninck AL, Gieschke R, Schoemaker RC, Roncari G, Tuk B, Pieters MS, et al. Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol. Br J Clin Pharmacol. 1996;41(6):565–73.

    PubMed  Google Scholar 

  18. Hollister LE. Interactions between alcohol and benzodiazepines. Recent Dev Alcohol. 1990;8:233–9.

    CAS  PubMed  Google Scholar 

  19. Siggins GR, Roberto M, Nie Z. The tipsy terminal: presynaptic effects of ethanol. Pharmacol Ther. 2005;107(1):80–98.

    CAS  PubMed  Google Scholar 

  20. Lovinger DM, Roberto M. Synaptic effects induced by alcohol. Curr Top Behav Neurosci. 2013;13:31–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Johnson EO, Roehrs T, Roth T, Breslau N. Epidemiology of alcohol and medication as aids to sleep in early adulthood. Sleep. 1998;21(2):178–86.

    CAS  PubMed  Google Scholar 

  22. Ancoli-Israel S, Roth T. Characteristics of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. I. Sleep. 1999;22(Suppl 2):S347–53.

    PubMed  Google Scholar 

  23. Stein MD, Friedmann PD. Disturbed sleep and its relationship to alcohol use. Subst Abuse. 2005;26(1):1–13.

    Google Scholar 

  24. Goodhines PA, Gellis LA, Kim J, Fucito LM, Park A. Self-medication for sleep in college students: concurrent and prospective associations with sleep and alcohol behavior. Behav Sleep Med. 2019;17(3):327–41.

    PubMed  Google Scholar 

  25. Roth T. Insomnia: definition, prevalence, etiology, and consequences. J Clin Sleep Med. 2007;3(5 Suppl):S7–10.

    PubMed  PubMed Central  Google Scholar 

  26. Roehrs T, Roth T. Sleep, sleepiness, and alcohol use. Alcohol Res Health. 2001;25(2):101–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ilomaki J, Paljarvi T, Korhonen MJ, Enlund H, Alderman CP, Kauhanen J, et al. Prevalence of concomitant use of alcohol and sedative-hypnotic drugs in middle and older aged persons: a systematic review. Ann Pharmacother. 2013;47(2):257–68.

    PubMed  Google Scholar 

  28. Wilkinson CJ. The acute effects of zolpidem, administered alone and with alcohol, on cognitive and psychomotor function. J Clin Psychiatry. 1995;56(7):309–18.

    CAS  PubMed  Google Scholar 

  29. Kuitunen T, Mattila MJ, Seppala T. Actions and interactions of hypnotics on human performance: single doses of zopiclone, triazolam and alcohol. Int Clin Psychopharmacol. 1990;5(Suppl 2):115–30.

    PubMed  Google Scholar 

  30. Linnoila M, Stapleon JM, Lister R, Moss H, Lane E, Granger A, et al. Effects of adinazolam and diazepam, alone and in combination with ethanol, on psychomotor and cognitive performance and on autonomic nervous system reactivity in healthy volunteers. Eur J Clin Pharmacol. 1990;38(4):371–7.

    CAS  PubMed  Google Scholar 

  31. Scavone JM, Greenblatt DJ, Harmatz JS, Shader RI. Kinetic and dynamic interaction of brotizolam and ethanol. Br J Clin Pharmacol. 1986;21(2):197–204.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Dorian P, Sellers EM, Kaplan HL, Hamilton C, Greenblatt DJ, Abernethy D. Triazolam and ethanol interaction: kinetic and dynamic consequences. Clin Pharmacol Ther. 1985;37(5):558–62.

    CAS  PubMed  Google Scholar 

  33. Kurzthaler I, Wambacher M, Golser K, Sperner G, Sperner-Unterweger B, Haidekker A, et al. Alcohol and benzodiazepines in falls: an epidemiological view. Drug Alcohol Depend. 2005;79(2):225–30.

    CAS  PubMed  Google Scholar 

  34. Kurzthaler I, Wambacher M, Golser K, Sperner G, Sperner-Unterweger B, Haidekker A, et al. Alcohol and/or benzodiazepine use: different accidents—different impacts? Hum Psychopharmacol. 2005;20(8):583–9.

    PubMed  Google Scholar 

  35. Orriols L, Philip P, Moore N, Castot A, Gadegbeku B, Delorme B, et al. Benzodiazepine-like hypnotics and the associated risk of road traffic accidents. Clin Pharmacol Ther. 2011;89(4):595–601.

    CAS  PubMed  Google Scholar 

  36. Sullivan SS, Guilleminault C. Emerging drugs for insomnia: new frontiers for old and novel targets. Expert Opin Emerg Drugs. 2009;14(3):411–22.

    CAS  PubMed  Google Scholar 

  37. Neubauer DN. New and emerging pharmacotherapeutic approaches for insomnia. Int Rev Psychiatry. 2014;26(2):214–24.

    PubMed  Google Scholar 

  38. Zoethout RW, van Gerven JM, Dumont GJ, Paltansing S, van Burgel ND, van der Linden M, et al. A comparative study of two methods for attaining constant alcohol levels. Br J Clin Pharmacol. 2008;66(5):674–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Zoethout RW, Schoemaker RC, Zuurman L, van Pelt H, Dahan A, Cohen AF, et al. Central nervous system effects of alcohol at a pseudo-steady-state concentration using alcohol clamping in healthy volunteers. Br J Clin Pharmacol. 2009;68(4):524–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. te Beek ET, Zoethout RW, Bani MS, Andorn A, Iavarone L, Klaassen ES, et al. Pharmacokinetics and central nervous system effects of the novel dopamine D3 receptor antagonist GSK598809 and intravenous alcohol infusion at pseudo-steady state. J Psychopharmacol. 2012;26(2):303–14.

    Google Scholar 

  41. European Transport Safety Council (ETSC). Blood Alcohol Content (BAC) Drink Driving Limits across Europe. https://etsc.eu/blood-alcohol-content-bac-drink-driving-limits-across-europe. Accessed 4 Dec 2019.

  42. Anderson P, Baumberg B. Alcohol in Europe—public health perspective: report summary. Drugs Educ Prev Policy. 2009;13(6):483–8.

    Google Scholar 

  43. Hoch M, Hay JL, Hoever P, de Kam ML, te Beek ET, van Gerven JM, et al. Dual orexin receptor antagonism by almorexant does not potentiate impairing effects of alcohol in humans. Eur Neuropsychopharmacol. 2013;23(2):107–17.

    CAS  PubMed  Google Scholar 

  44. Watson PE, Watson ID, Batt RD. Total body water volumes for adult males and females estimated from simple anthropometric measurements. Am J Clin Nutr. 1980;33(1):27–39.

    CAS  PubMed  Google Scholar 

  45. O’Connor S, Morzorati S, Christian J, Li TK. Clamping breath alcohol concentration reduces experimental variance: application to the study of acute tolerance to alcohol and alcohol elimination rate. Alcohol Clin Exp Res. 1998;22(1):202–10.

    PubMed  Google Scholar 

  46. Mulder JA, Neuteboom W, Wessel RM. Breath alcohol legislation in The Netherlands. Blutalkohol. 1991;28(2):94–107.

    CAS  PubMed  Google Scholar 

  47. van Steveninck AL, van Berckel BN, Schoemaker RC, Breimer DD, van Gerven JM, Cohen AF. The sensitivity of pharmacodynamic tests for the central nervous system effects of drugs on the effects of sleep deprivation. J Psychopharmacol. 1999;13(1):10–7.

    PubMed  Google Scholar 

  48. Zuurman L, Roy C, Schoemaker RC, Hazekamp A, den Hartigh J, Bender JC, et al. Effect of intrapulmonary tetrahydrocannabinol administration in humans. J Psychopharmacol. 2008;22(7):707–16.

    CAS  PubMed  Google Scholar 

  49. Borland RG, Nicholson AN. Visual motor co-ordination and dynamic visual acuity. Br J Clin Pharmacol. 1984;18(Suppl 1):69S–72S.

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  51. de Haas SL, Schoemaker RC, van Gerven JM, Hoever P, Cohen AF, Dingemanse J. Pharmacokinetics, pharmacodynamics and the pharmacokinetic/pharmacodynamic relationship of zolpidem in healthy subjects. J Psychopharmacol. 2010;24(11):1619–29.

    PubMed  Google Scholar 

  52. Wright BM. A simple mechanical ataxia-meter. J Physiol. 1971;218(Suppl):27–28P.

    Google Scholar 

  53. Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br J Med Psychol. 1974;47(3):211–8.

    Google Scholar 

  54. de Visser SJ, van der Post J, Pieters MS, Cohen AF, van Gerven JM. Biomarkers for the effects of antipsychotic drugs in healthy volunteers. Br J Clin Pharmacol. 2001;51(2):119–32.

    PubMed  PubMed Central  Google Scholar 

  55. Norris H. The action of sedatives on brain stem oculomotor systems in man. Neuropharmacology. 1971;10(21):181–91.

    CAS  PubMed  Google Scholar 

  56. Bourgeois BFD. Antiepileptic drugs: combination therapy and interactions. Cambridge: Cambridge University Press; 2005.

    Google Scholar 

  57. Sun H, Yee KL, Gill S, Liu W, Li X, Panebianco D, et al. Psychomotor effects, pharmacokinetics and safety of the orexin receptor antagonist suvorexant administered in combination with alcohol in healthy subjects. J Psychopharmacol. 2015;29(11):1159–69.

    CAS  PubMed  Google Scholar 

  58. Pfeiffer A, Hogl B, Kaess H. Effect of ethanol and commonly ingested alcoholic beverages on gastric emptying and gastrointestinal transit. Clin Investig. 1992;70(6):487–91.

    CAS  PubMed  Google Scholar 

  59. Kasicka-Jonderko A, Jonderko K, Bozek M, Kaminska M, Mglosiek P. Potent inhibitory effect of alcoholic beverages upon gastrointestinal passage of food and gallbladder emptying. J Gastroenterol. 2013;48(12):1311–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Beck IT, Dinda PK. Acute exposure of small intestine to ethanol: effects on morphology and function. Dig Dis Sci. 1981;26(9):817–38.

    CAS  PubMed  Google Scholar 

  61. Greenblatt DJ, Sahder RI, Weinberger DR, Allen MD, MacLaughlin DS. Effect of a cocktail on diazepam absorption. Psychopharmacology. 1978;57(2):199–203.

    CAS  PubMed  Google Scholar 

  62. Morasso MI, Chavez J, Gai MN, Arancibia A. Influence of alcohol consumption on erythromycin ethylsuccinate kinetics. Int J Clin Pharmacol Ther Toxicol. 1990;28(10):426–9.

    CAS  PubMed  Google Scholar 

  63. The Medical Letter. Lemborexant (Dayvigo) for insomnia. Med Lett Drugs Ther. 2020;62(1601):97–100.

    Google Scholar 

  64. Hoever P, de Haas SL, Dorffner G, Chiossi E, van Gerven JM, Dingemanse J. Orexin receptor antagonism: an ascending multiple-dose study with almorexant. J Psychopharmacol. 2012;26(8):1071–80.

    PubMed  Google Scholar 

  65. Groeneveld GJ, Hay JL, Van Gerven JM. Measuring blood-brain barrier penetration using the NeuroCart, a CNS test battery. Drug Discov Today Technol. 2016;20:27–34.

    PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the study team at the CHDR (Leiden, The Netherlands) for the clinical conduct of this study; Radka Štěpánová (Aixial s.r.o., Brno, Czech Republic) for statistical analysis of the clinical data; and Susanne Globig (Department of Preclinical Pharmacokinetics and Metabolism, Idorsia Pharmaceuticals Ltd) for the bioanalytical conduct of daridorexant. Last but not least, the authors thank the clinical research team, i.e., Alexandre Mathis, István Kerekes, Pascale Gasser, and Marie Stoffel (Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd).

Author information

Author notes

  1. Benjamin Berger and Sander Brooks contributed equally to this body of work.

Authors and Affiliations

  1. Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland

    Benjamin Berger, Muriel Richard, Clemens Muehlan & Jasper Dingemanse

  2. Centre for Human Drug Research (CHDR), Leiden, The Netherlands

    Sander Brooks & Rob Zuiker

  3. Leiden University Medical Center, Leiden, The Netherlands

    Sander Brooks

Authors
  1. Benjamin Berger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sander Brooks
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rob Zuiker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Muriel Richard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Clemens Muehlan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jasper Dingemanse
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benjamin Berger.

Ethics declarations

Funding

This study was funded by Idorsia Pharmaceuticals Ltd.

Conflicts of Interest

Benjamin Berger, Muriel Richard, Clemens Muehlan, and Jasper Dingemanse were full-time employees of Idorsia Pharmaceuticals Ltd at the time of study conduct. Muriel Richard, Clemens Muehlan, and Jasper Dingemanse own stocks in Idorsia Pharmaceuticals Ltd, and Clemens Muehlan and Jasper Dingemanse own stock options in Idorsia Pharmaceuticals Ltd. Sander Brooks and Rob Zuiker were employees of CHDR at the time of study conduct. There are no other relationships or activities that could appear to have influenced the submitted work. CHDR received financial compensation for conducting the study from Idorsia Pharmaceuticals Ltd.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study prior to any study-mandated procedure.

Availability of Data and Material

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions

MR and JD designed the study. BB and SB wrote the manuscript. SB and RZ performed the assessments and collected the data. Data were analyzed by BB, CM, SB, and RZ. All authors reviewed and approved the final manuscript.

Additional information

The authors confirm that the Principal Investigator for this study is Rob Zuiker and that he had direct clinical responsibility for the subjects.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Berger, B., Brooks, S., Zuiker, R. et al. Pharmacological Interactions between the Dual Orexin Receptor Antagonist Daridorexant and Ethanol in a Double-Blind, Randomized, Placebo-Controlled, Double-Dummy, Four-Way Crossover Phase I Study in Healthy Subjects. CNS Drugs 34, 1253–1266 (2020). https://doi.org/10.1007/s40263-020-00768-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-020-00768-8

Search

Navigation