Dual orexin receptor antagonism by almorexant does not potentiate impairing effects of alcohol in humans.
The orexin system plays a pivotal role in the regulation of the sleep/wake state. Almorexant is a selective, orally available dual orexin receptor antagonist. This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between almorexant (200 mg p.o.) and alcohol (0.6 g/L i.v. ethanol clamp for 5 h) using various cognitive and psychomotor performance tests in healthy subjects (n=20; 10 males and 10 females) in a 4-way crossover study. No effect of almorexant on ethanol PK was observed. The effects of ethanol on the PK of almorexant were limited, its exposure (AUC) increased by 21%; the median difference in tmax was 1.2 h; t1/2 and Cmax of almorexant were unchanged. Almorexant showed decreases in adaptive tracking performance, saccadic peak velocity, and subjective alertness as assessed by visual analog scale (VAS) of Bond and Lader, but had no or small effects on smooth pursuit eye movements, body sway, VAS for alcohol intoxication, and a memory test. Almorexant administered together with ethanol showed additive effects for adaptive tracking performance, saccadic peak velocity, subjective alertness and, possibly, calmness, but not on body sway, smooth pursuit, VAS for alcohol intoxication, or memory testing. To conclude, administration of almorexant together with ethanol was associated with additive effects for some of the measured cognitive and psychomotor performance tests. No indications of synergistic effects of almorexant and ethanol for any measured variable were observed.
Actelion Pharmaceuticals Ltd., Clinical Pharmacology, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. matthias.hoch@actelion.com
Matthias
M
Hoch
Justin L
JL
Hay
Petra
P
Hoever
Marieke L
ML
de Kam
Erik T
ET
te Beek
Joop M A
JM
van Gerven
Jasper
J
Dingemanse
D000081:Acetamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000339:Affect / Q000187:drug effects; D000435:Alcoholic Intoxication / Q000188:drug therapy; D001143:Arousal / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004357:Drug Synergism; D000431:Ethanol / Q000009:adverse effects / Q000819:agonists* / Q000493:pharmacokinetics / Q000494:pharmacology; D005133:Eye Movements / Q000187:drug effects; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008568:Memory / Q000187:drug effects; D008875:Middle Aged; D000068796:Orexin Receptor Antagonists; D011187:Posture; D011597:Psychomotor Performance / Q000187:drug effects*
D000081:Acetamides; D007546:Isoquinolines; D000068796:Orexin Receptor Antagonists; D000431:Ethanol; C519150:almorexant