Impact of Daridorexant, a Dual Orexin Receptor Antagonist, on Cardiac Repolarization Following Bedtime Dosing: Results from a Thorough QT Study Using Concentration-QT Analysis.

Autor: Schilling U; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland., Henrich A; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland., Muehlan C; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland., Krause A; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland., Dingemanse J; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland. jasper.dingemanse@idorsia.com., Ufer M; Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
Jazyk: angličtina
Zdroj: Clinical drug investigation [Clin Drug Investig] 2021 Aug; Vol. 41 (8), pp. 711-721. Date of Electronic Publication: 2021 Jul 31.
DOI: 10.1007/s40261-021-01062-1
Abstrakt: Background and Objective: Daridorexant is a new dual orexin receptor antagonist currently in late-stage clinical development for the treatment of insomnia. This randomized, double-blind, placebo-controlled, four-period crossover study investigated the effect of daridorexant at a therapeutic and supratherapeutic dose on QT interval duration.
Methods: Thirty-six healthy subjects received single oral doses of daridorexant (50 mg; 200 mg), moxifloxacin (400 mg; open label), and placebo. All treatments were administered at bedtime to mimic therapeutic practice. The primary analysis was based on linear mixed-effects concentration-QT modelling. Triplicate ECG data were extracted from Holter recordings at baseline and until 24 h post dosing at time points matching those for pharmacokinetic sampling. Plasma concentrations of daridorexant were determined over 24 h.
Results: Assay sensitivity was demonstrated based on mean baseline- and placebo-corrected QT interval using Fridericia's formula (ΔΔQTcF) > 5 ms following moxifloxacin administration (p < 0.01). Following daridorexant administration, mean (90% confidence interval, CI) ΔΔQTcF was 1.40 ms (0.48; 2.32 ms) and 1.84 ms (-0.12; 3.79 ms) at the C max of 747 ng/mL (50 mg dose) and 1809 ng/mL (200 mg dose), respectively, i.e., the upper bounds of the CIs were < 10 ms defined as threshold of regulatory concern. Lack of relevant QT prolongation was confirmed by secondary by-time point analysis and absence of relevant findings in the categorical outlier analysis. Daridorexant was safe and well tolerated and its pharmacokinetics were consistent with previous data.
Conclusion: Daridorexant does not impair cardiac repolarization evidenced by absence of relevant QT prolongation at therapeutic and supratherapeutic doses. Clinical Trials Registration ID: NCT04250506.
(© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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