title: Pharmacokinetic interactions between the orexin receptor antagonist almorexant and the CYP3A4 inhibitors ketoconazole and diltiazem.
abstract: Almorexant, a tetrahydroisoquinoline orexin receptor antagonist and first representative of a new class of compounds for the treatment of insomnia, is a substrate of the cytochrome P450 3A4 isoenzyme (CYP3A4). Two randomized two-way crossover studies were performed in healthy subjects investigating the pharmacokinetic interaction between almorexant and the CYP3A4 inhibitors ketoconazole and diltiazem. When administered as a single dose of 100 mg almorexant during steady state of ketoconazole (400 mg once daily for 14 days) or diltiazem treatment (300 mg once daily for 11 days), the exposure to almorexant was 10.5- and 3.5-fold, respectively, greater when compared with almorexant alone. Exposure to the phenol metabolites M3 and M8 increased in the presence of the CYP3A4 inhibitors, whereas that to M6 (dealkylated metabolite) decreased. Concomitant ketoconazole decreased formation of the dehydrogenated metabolite M5 and diltiazem increased concentrations of this metabolite. Higher almorexant exposure was associated with an increased incidence of typical almorexant-related adverse events such as fatigue (both studies) and somnolence (ketoconazole study only). The present results indicate that dose adaptation must be considered when almorexant would be coadministered with inhibitors of CYP3A4.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
authors.forename: Hans Gabriel
authors.initials: HG
authors.lastname: Cruz
authors.forename: Martine
authors.initials: M
authors.lastname: Gehin
authors.forename: Petra
authors.initials: P
authors.lastname: Hoever
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004110:Diltiazem / Q000493:pharmacokinetics*; D004347:Drug Interactions / Q000502:physiology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D007546:Isoquinolines / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000493:pharmacokinetics*; D008297:Male; D000068796:Orexin Receptor Antagonists; D055815:Young Adult
chemical_list: D000081:Acetamides; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D000068796:Orexin Receptor Antagonists; C519150:almorexant; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004110:Diltiazem; D007654:Ketoconazole
keywords: almorexant; cytochrome P450 3A4; diltiazem; disposition; drug interaction; healthy subjects; ketoconazole; metabolism; orexin receptor antagonist; pharmacokinetics