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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.
AuthorsJasper Dingemanse, Hans Gabriel Cruz, Martine Gehin, Petra Hoever
JournalJournal of pharmaceutical sciences (J Pharm Sci) Vol. 103 Issue 5 Pg. 1548-56 (May 2014) ISSN: 1520-6017 [Electronic] United States
PMID24604243 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Copyright© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.
Chemical References
  • Acetamides
  • Enzyme Inhibitors
  • Isoquinolines
  • Orexin Receptor Antagonists
  • almorexant
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Diltiazem
  • Ketoconazole
Topics
  • Acetamides (pharmacokinetics)
  • Adult
  • Area Under Curve
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A (metabolism)
  • Diltiazem (pharmacokinetics)
  • Drug Interactions (physiology)
  • Enzyme Inhibitors (pharmacokinetics)
  • Humans
  • Isoquinolines (pharmacokinetics)
  • Ketoconazole (pharmacokinetics)
  • Male
  • Orexin Receptor Antagonists
  • Young Adult

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