PMID- 33205362
OWN - NLM
STAT- MEDLINE
DCOM- 20211020
LR  - 20211020
IS  - 1179-1934 (Electronic)
IS  - 1172-7047 (Linking)
VI  - 34
IP  - 12
DP  - 2020 Dec
TI  - 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.
PG  - 1253-1266
LID - 10.1007/s40263-020-00768-8 [doi]
AB  - 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 (t(max)) 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 
      t(max), 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).
FAU - Berger, Benjamin
AU  - Berger B
AUID- ORCID: 0000-0001-7777-5734
AD  - Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, 
      Hegenheimermattweg 91, 4123, Allschwil, Switzerland. benjamin.berger@idorsia.com.
FAU - Brooks, Sander
AU  - Brooks S
AUID- ORCID: 0000-0003-3539-2908
AD  - Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
AD  - Leiden University Medical Center, Leiden, The Netherlands.
FAU - Zuiker, Rob
AU  - Zuiker R
AUID- ORCID: 0000-0001-5604-0157
AD  - Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
FAU - Richard, Muriel
AU  - Richard M
AUID- ORCID: 0000-0003-0295-7730
AD  - Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, 
      Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
FAU - Muehlan, Clemens
AU  - Muehlan C
AUID- ORCID: 0000-0002-0788-3788
AD  - Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, 
      Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
FAU - Dingemanse, Jasper
AU  - Dingemanse J
AUID- ORCID: 0000-0002-4083-5817
AD  - Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, 
      Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
LA  - eng
SI  - ClinicalTrials.gov/NCT03609775
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20201118
PL  - New Zealand
TA  - CNS Drugs
JT  - CNS drugs
JID - 9431220
RN  - 0 (Imidazoles)
RN  - 0 (Orexin Receptor Antagonists)
RN  - 0 (Pyrrolidines)
RN  - 0 (daridorexant)
RN  - 3K9958V90M (Ethanol)
SB  - IM
MH  - Adult
MH  - Cross-Over Studies
MH  - Double-Blind Method
MH  - Drug Interactions
MH  - Ethanol/adverse effects/*pharmacology
MH  - Female
MH  - Humans
MH  - Imidazoles/adverse effects/pharmacokinetics/*pharmacology
MH  - Male
MH  - Orexin Receptor Antagonists/adverse effects/*pharmacology
MH  - Pyrrolidines/adverse effects/pharmacokinetics/*pharmacology
MH  - Young Adult
EDAT- 2020/11/19 06:00
MHDA- 2021/10/21 06:00
CRDT- 2020/11/18 06:03
PHST- 2020/09/23 00:00 [accepted]
PHST- 2020/11/19 06:00 [pubmed]
PHST- 2021/10/21 06:00 [medline]
PHST- 2020/11/18 06:03 [entrez]
AID - 10.1007/s40263-020-00768-8 [pii]
AID - 10.1007/s40263-020-00768-8 [doi]
PST - ppublish
SO  - CNS Drugs. 2020 Dec;34(12):1253-1266. doi: 10.1007/s40263-020-00768-8. Epub 2020 
      Nov 18.