Multiple-dose clinical pharmacology of ACT-541468, a novel dual orexin receptor antagonist, following repeated-dose morning and evening administration

Muehlan, Clemens; Brooks, Sander; Zuiker, Rob; Gerven, Joop van; Dingemanse, Jasper

doi:10.1016/j.euroneuro.2019.05.009

Cited by 48 publications

(77 citation statements)

References 35 publications

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“…Suvorexant, developed by Merck is on the market since 2014 and no other orexin receptor antagonist had been approved by the FDA since. Intense research led to compounds currently investigated in late stage clinical trials for the treatment of insomnia, e. g. lemborexant ( 2 ) from Eisai or daridorexant ( 3 ) from Idorsia, both DORA's inhibiting orexin 1 and orexin 2 receptors (OX 1 R and OX 2 R, respectively). Seltorexant ( 4 ), a selective OX 2 R antagonist co‐developed by Janssen and Minerva Neurosciences is as well in clinical development for the treatment of insomnia .…”

Section: Introductionmentioning

confidence: 99%

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

et al. 2020

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The orexin system is responsible for regulating the sleep‐wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5‐methoxy‐4‐methyl‐2‐[1,2,3]triazol‐2‐yl‐phenyl)‐{(S)‐2‐[5‐(2‐trifluoromethoxy‐phenyl)‐[1,2,4]oxadiazol‐3‐yl]‐pyrrolidin‐1‐yl}methanone (6), a compound which emerged from our in‐house research program. Compound 6 was shown to be a potent, brain‐penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (fu brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above‐mentioned shortcomings resulted in the identification of (4‐chloro‐2‐[1,2,3]triazol‐2‐yl‐phenyl)‐{(S)‐2‐methyl‐2‐[5‐(2‐trifluoromethoxy‐phenyl)‐4H‐[1,2,4]triazol‐3‐yl]‐pyrrolidin‐1‐yl}l‐methanone (42), a DORA with improved in vivo efficacy compared to 6.

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Section: Introductionmentioning

confidence: 99%

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

et al. 2020

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“…10 Mean total peak plasma concentrations at a dose of 75 mg daridorexant (50% higher than the highest dose in Phase 3) were 1308 ng/ mL, equivalent to 2.9 µmol/L. 6 Considering the high plasma protein binding of 99.9% determined ex vivo and the resulting low unbound mean plasma concentrations in the low nanomolar range, ie, significantly below the IC 50 value of 3.0 µmol/Lobserved for BCRP inhibition, daridorexant was not expected to inhibit BCRP in the liver or the kidney. However, the extent of any effect of daridorexant on the activity of intestinal BCRP remained unknown.…”

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confidence: 99%

“…5 Prior to the present study, daridorexant was clinically evaluated in five Phase 1 studies, in which a total of 162 healthy young adults and healthy elderly subjects were enrolled and treated with single or multiple doses of up to 200 mg or 75 mg, respectively. 3,[6][7][8] Daridorexant was safe and well tolerated with a pharmacokinetic (PK) profile characterized by a quick absorption and elimination, with median time to reach maximum concentration (t max ) of 1-3 hours and geometric mean terminal half-life (t 1/2 ) of 6-10 hours. 3,6 Using a validated pharmacodynamic (PD) test battery, clear dose-dependent effects on the central nervous system, ie, reduced vigilance and attention, alertness, and motor coordination were observed.…”

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confidence: 99%

“…3,[6][7][8] Daridorexant was safe and well tolerated with a pharmacokinetic (PK) profile characterized by a quick absorption and elimination, with median time to reach maximum concentration (t max ) of 1-3 hours and geometric mean terminal half-life (t 1/2 ) of 6-10 hours. 3,6 Using a validated pharmacodynamic (PD) test battery, clear dose-dependent effects on the central nervous system, ie, reduced vigilance and attention, alertness, and motor coordination were observed. 6 The metabolism of daridorexant is mostly dependent on cytochrome P450 3A4 (CYP3A4).…”

mentioning

confidence: 99%

“…3,6 Using a validated pharmacodynamic (PD) test battery, clear dose-dependent effects on the central nervous system, ie, reduced vigilance and attention, alertness, and motor coordination were observed. 6 The metabolism of daridorexant is mostly dependent on cytochrome P450 3A4 (CYP3A4). 7 Oral administration of 14 C-labelled daridorexant showed that excretion in faeces was the major elimination pathway of daridorexant accounting for a mean recovery of 57% of the administered radioactive dose, while 28% was found in urine.…”

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confidence: 99%

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The dual orexin receptor antagonist daridorexant does not affect the pharmacokinetics of the BCRP substrate rosuvastatin

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Muehlan

Ulč³

et al. 2020

Clin Exp Pharma Physio

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The orexin system was discovered in 1998, and it involves the neuropeptides orexin A and orexin B, that are synthesized in the lateral hypothalamic area, which projects to various regions in the brain and that binds two G protein-coupled receptors orexin-1 (OX1) and orexin-2 (OX2). 1 This system is thought to play a role in the regulation of arousal and sleep-wake balance. 1,2 Daridorexant (ACT-541468) is a dual orexin receptor antagonist currently in clinical development for the treatment of insomnia. 3,4 The compound

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Driving Performance after Bedtime Administration of Daridorexant, Assessed in a Sensitive Simulator

Muehlan

Brooks

Vaillant

et al. 2022

Clin Pharma and Therapeutics

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Use of hypnotics is often associated with next-morning residual effects and a higher risk of motor vehicle accidents. Measuring next-morning effects on driving performance is therefore advised by regulatory agencies. Here, we examined driving performance following administration of daridorexant, a new dual orexin receptor antagonist developed to treat insomnia. Sixty healthy male and female subjects (50-79 years of age) were randomized in a placebo-and active-controlled, four-way cross-over study. Each subject received evening administration of daridorexant 50 and 100 mg, zopiclone 7.5 mg, and placebo, in separate treatment phases of 4 days. Simulated driving performance was assessed after initial (day 2) and repeated dosing (day 5), 9 hours postdose. Standard deviation of the lateral position (SDLP) was the main outcome. On both days, with zopiclone, SDLP increased significantly compared with placebo, which confirmed sensitivity of the simulator. With daridorexant, on day 2, the placebo-corrected mean (97.5% confidence interval) SDLP increased by 2.19 cm (0.46-3.93) and 4.43 cm (2.72-6.15) for 50 and 100 mg, respectively. On day 5, SDLP values for both daridorexant doses were significantly below the prespecified threshold of impairment (2.6 cm) and statistically not different from placebo. Daridorexant showed a lower self-rated driving quality and higher effort compared to placebo on day 2 but not on day 5. In non-insomnia subjects, daridorexant impaired simulated driving after initial but not after repeated dosing. Subjects should be cautioned about driving until they know how daridorexant affects them.

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Multiple-dose clinical pharmacology of ACT-541468, a novel dual orexin receptor antagonist, following repeated-dose morning and evening administration

Cited by 48 publications

References 35 publications

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

The dual orexin receptor antagonist daridorexant does not affect the pharmacokinetics of the BCRP substrate rosuvastatin

Driving Performance after Bedtime Administration of Daridorexant, Assessed in a Sensitive Simulator

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