title: Pharmacokinetic and pharmacodynamic interactions between almorexant, a dual orexin receptor antagonist, and desipramine.
abstract: Almorexant is a dual orexin receptor antagonist (DORA) with sleep-enabling effects in humans. Insomnia is often associated with mental health problems, including depression. Hence, potential interactions with antidepressants deserve attention. Desipramine was selected as a model drug because it is mainly metabolized by CYP2D6, which is inhibited by almorexant in vitro. A single-center, randomized, placebo-controlled, two-way crossover study in 20 healthy male subjects was conducted to evaluate the pharmacokinetic and pharmacodynamic interactions between almorexant and desipramine. Almorexant 200mg or matching placebo (double-blind) was administered orally once daily in the morning for 10 days, and a single oral dose of 50mg desipramine (open-label) was administered on Day 5. Almorexant increased the exposure to desipramine 3.7-fold, suggesting that almorexant is a moderate inhibitor of desipramine metabolism through inhibition of CYP2D6. Conversely, desipramine showed no relevant effects on the pharmacokinetics of almorexant. Pharmacodynamic evaluations indicated that almorexant alone reduced visuomotor coordination, postural stability, and alertness, and slightly increased calmness. Desipramine induced a reduction in subjective alertness and an increase in pupil/iris ratio. Despite the increase in exposure to desipramine, almorexant and desipramine in combination showed the same pharmacodynamic profile as almorexant alone, except for prolonging reduced alertness and preventing the miotic effect of almorexant. Co-administration also prolonged the mydriatic effect of desipramine. Overall, repeated administration of almorexant alone or with single-dose desipramine was well tolerated. The lack of a relevant interaction with antidepressants, if confirmed for other DORAs, would be a key feature for a safer class of hypnotics.
authors.affiliation: Actelion Pharmaceuticals Ltd, Clinical Pharmacology, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Cruz
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Hay
authors.affiliation: Actelion Pharmaceuticals Ltd, Clinical Pharmacology, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Hoever
authors.affiliation: Actelion Pharmaceuticals Ltd, Biostatistics, Allschwil, Switzerland.
authors.forename: Federica
authors.initials: F
authors.lastname: Alessi
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Erik T
authors.initials: ET
authors.lastname: te Beek
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Joop M A
authors.initials: JM
authors.lastname: van Gerven
authors.affiliation: Actelion Pharmaceuticals Ltd, Clinical Pharmacology, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. Electronic address: jasper.dingemanse@actelion.com.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics*; D001769:Blood / Q000187:drug effects*; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003891:Desipramine / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D007546:Isoquinolines / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D000068796:Orexin Receptor Antagonists; D055815:Young Adult
chemical_list: D000081:Acetamides; D000929:Antidepressive Agents, Tricyclic; D007546:Isoquinolines; D000068796:Orexin Receptor Antagonists; C519150:almorexant; D019389:Cytochrome P-450 CYP2D6; D003891:Desipramine
keywords: Almorexant; Desipramine; Interaction; Orexin; Pharmacodynamics; Pharmacokinetics