ArticleDrugs in R&D2024
Effect of Daridorexant on the Pharmacokinetics of Midazolam, and on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects.
Article in Drugs in R&D, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05480488 (A Single-center, Open-label Study to Investigate the Effect of Single- and Multiple-dose Daridorexant on the Pharmacokinetics of Midazolam and Its Metabolite 1-hydroxymidazolam, and the Effect of Single-dose Daridorexant on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects), which is not on this map. Not yet cited in PubMed.
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A Single-center, Open-label Study to Investigate the Effect of Single- and Multiple-dose Daridorexant on the Pharmacokinetics of Midazolam and Its Metabolite 1-hydroxymidazolam, and the Effect of Single-dose Daridorexant on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects
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5 authors at 2 institutions in 2 countries.
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Abstract
BACKGROUND AND
objectivesDaridorexant, a dual orexin receptor antagonist was recently approved for the treatment of insomnia at doses up to 50 mg once per night. This study investigated the effect of single-dose and multiple-dose daridorexant 50 mg at steady state on the pharmacokinetics (PK) of the cytochrome P450 (CYP) 3A4-sensitive substrate midazolam, and the effect of single-dose daridorexant 50 mg on the PK and pharmacodynamics (PD) of the CYP2C9-sensitive substrate warfarin.
methodsIn this prospective, single-center, open-label, fixed-sequence, phase I, drug-drug interaction study, 18 healthy male subjects sequentially received Treatment A, B, and C in three periods. Treatment A consisted of a single oral concomitant administration of midazolam 2 mg and warfarin 25 mg on day 1 of the first period. Treatment B consisted of one oral administration of daridorexant 50 mg followed 1 h later by a single oral dose of midazolam 2 mg concomitantly with a single oral dose of warfarin 25 mg on day 1 and a once-daily oral administration of daridorexant 50 mg for 6 days of the second period. Treatment C consisted of a single oral administration of daridorexant 50 mg at steady state followed 1 h later by a single oral administration of midazolam 2 mg on day 1 of the third period. Blood samples were assessed for midazolam and S-warfarin PK, and PD (international normalized ratio and factor VII). Noncompartmental PK parameters and PD variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment B/A versus C/A for midazolam, and treatment B/A for warfarin. Safety and tolerability of each treatment were also assessed.
resultsMidazolam maximum plasma concentration (C
conclusionsDaridorexant at 50 mg is classified as a weak CYP3A4 inhibitor after single- and multiple-dose administration once daily at steady state. Daridorexant 50 mg did not induce CYP3A4 activity or inhibit CYP2C9 activity. CLINICAL
trial registrationThis trial (NCT05480488) was registered on 29 July, 2022.
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