Absolute oral bioavailability of almorexant, a dual orexin receptor antagonist, in healthy human subjects.
OBJECTIVE
The aim of this single-center, open-label study was to assess the absolute bioavailability of an oral (tablet) versus intravenous formulation of almorexant in healthy subjects.


METHODS
A pilot phase in 3 healthy male subjects, which preceded the main study, consisted of a single 30-min intravenous infusion of 10 mg almorexant. Its objectives were to ensure the tolerability of the intravenous formulation and to select the intravenous dose for the main study. The main study was a randomized, two-way crossover study in 20 healthy subjects (10 males and 10 females). Subjects received a single oral dose of 200 mg almorexant and a single 30-min intravenous infusion of 20 mg almorexant.


RESULTS
All 23 subjects completed the study as planned. Almorexant was well tolerated; the main observed adverse events were somnolence and fatigue. A geometric mean total body clearance of 43 l/h (95% CI 39-47) and a volume of distribution of 683 liters (95% CI 552-845) were determined. The absolute oral bioavailability of almorexant was 11.2% (90% CI 9.6-13.1).


CONCLUSIONS
Almorexant seems to possess a pronounced first-pass effect and metabolism.
Actelion Pharmaceuticals Ltd., Clinical Pharmacology, Allschwil, Switzerland. matthias.hoch@actelion.com
Matthias
M
Hoch
Petra
P
Hoever
Jochen
J
Zisowsky
Anthony
A
Priestley
David
D
Fleet
Jasper
J
Dingemanse
D000081:Acetamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*
D000081:Acetamides; D006993:Hypnotics and Sedatives; D007546:Isoquinolines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C519150:almorexant