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Clinical assessment of drug–drug interactions of tasimelteon, a novel dual melatonin receptor agonist
Author(s) -
Ogilvie Brian W.,
Torres Rosarelis,
Dressman Marlene A.,
Kramer William G.,
Baroldi Paolo
Publication year - 2015
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.507
Subject(s) - pharmacology , pharmacokinetics , agonist , melatonin , drug , cyp3a4 , chemistry , ketoconazole , melatonin receptor , bioavailability , receptor , cyp1a2 , area under the curve , cytochrome p450 , medicine , biochemistry , metabolism , antifungal , dermatology
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 (MT 1 and MT 2 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%.