title: Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist.
abstract: Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug-drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%.
authors: XenoTech, LLC, Lenexa, KS, USA.
authors: Brian W
authors: BW
authors: Ogilvie
authors: Vanda Pharmaceuticals, Inc., Washington, DC, USA.
authors: Rosarelis
authors: R
authors: Torres
authors: Vanda Pharmaceuticals, Inc., Washington, DC, USA.
authors: Marlene A
authors: MA
authors: Dressman
authors: Kramer Consulting LLC, North Potomac, MD, USA.
authors: William G
authors: WG
authors: Kramer
authors: Vanda Pharmaceuticals, Inc., Washington, DC, USA.
authors: Paolo
authors: P
authors: Baroldi
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001572:Benzofurans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D003521:Cyclopropanes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D065609:Cytochrome P-450 CYP1A2 Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage / Q000493:pharmacokinetics; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D016666:Fluvoxamine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D044094:Receptors, Melatonin / Q000819:agonists*; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012907:Smoking / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D001572:Benzofurans; D003521:Cyclopropanes; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D044094:Receptors, Melatonin; D016666:Fluvoxamine; D007654:Ketoconazole; C478745:tasimelteon; D012293:Rifampin
keywords: Non-24; Non-24-Hour Sleep-Wake Disorder; cytochrome P450; drug-drug interactions; dual melatonin receptor agonists; pharmacokinetics; tasimelteon