Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders

  title={Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders},
  author={Clemens Muehlan and Cedric Vaillant and Isabelle Zenklusen and Stephan Kraehenbuehl and Jasper Dingemanse},
  journal={Expert Opinion on Drug Metabolism \& Toxicology},
  pages={1063 - 1078}
ABSTRACT Introduction The last two decades have witnessed a rapid increase in the knowledge about the role of the orexin system, particularly in the regulation of wakefulness and arousal. Dual orexin receptor antagonists (DORAs) have been approved for the treatment of insomnia disorders (suvorexant, lemborexant) and drugs with a distinctive profile (daridorexant) or orexin-2 receptor selectivity (seltorexant) are in development. Areas covered This review discusses pharmacokinetics (PK… 

Dual orexin receptor antagonist in treatment of insomnia

A novel group of medications, dual orexin receptor antagonists, emerged as a competent group that challenges current first-line hypnotics, with the advantage over conventional hypnotics stems from the specifics of their target receptors, which translates into lack of tolerance after long term use and good safety profile.

Daridorexant for the Treatment of Insomnia.

Daridorexant is a dual orexin type 1 and types 2 (OX1 and OX2) receptor antagonist that was recently approved by the US FDA for the treatment of adults suffering from insomnia and was shown to be effective in reducing insomnia symptoms, increasing daytime functioning, and improving the overall quality of sleep.

Effect of Liver Cirrhosis on the Pharmacokinetics, Metabolism, and Tolerability of Daridorexant, A Novel Dual Orexin Receptor Antagonist

A dose adjustment is not required in Child–Pugh A patients, while avoidance of daridorexant in patients with Child-Pugh C cirrhosis is recommended, a premise that dual orexin receptor antagonists may fulfill.

Pharmacokinetics of daridorexant, a dual orexin receptor antagonist, are not affected by renal impairment

The aim of this study was to evaluate the impact of renal impairment on the pharmacokinetics (PKs), safety, and tolerability of daridorexant, a dual orexin receptor antagonist intended for the

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

Daridorexant does not impair cardiac repolarization evidenced by absence of relevant QT prolongation at therapeutic and supratherapeutic doses and its pharmacokinetics were consistent with previous data.

Agonists and antagonists of the orexinergic system: therapeutic molecules of the future - a narrative review

This review focuses on the therapeutic roles of OXs as agonists or antagonists in animal models and human patients, which can lead to possible avenues related to their application in health and disease.

Effect of the new dual orexin receptor antagonist daridorexant on nighttime respiratory function and sleep in patients with mild and moderate obstructive sleep apnea.

The results indicate that single and repeated doses of 50 mg daridorexant do not impair nighttime respiratory function and improve sleep in patients with mild and moderate OSA.

Orexin receptors: Targets and applications.

The structure of orexin receptors, their physiological role and various applications in disease states are discussed, adding a note on agonists and antagonists and finally summarizing the recent drug approvals in the field.

Emerging therapeutic targets for narcolepsy

This review discusses various emerging treatment targets for narcolepsy and the focus is on the Hcrt receptors but included are also wake-promoting pathways, and sleep-stabilization through GABAergic mechanisms.



The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia.

Among DORAs evaluated clinically, suvorexant has pharmacokinetic properties engineered for a plasma half-life appropriate for rapid sleep onset and maintenance at low to moderate doses, and the preservation of cognitive performance and the ability to arouse to salient stimuli after DORA administration suggest further advantages over historical therapies.

Pharmacotherapy of Insomnia with Ramelteon: Safety, Efficacy and Clinical Applications

The efficacy and safety of ramelteon in patients with chronic insomnia was initially confirmed in short-term placebo-controlled trials, and a 6-month placebo- controlled international study and a 1-year open-label study in the USA demonstrated that ramelTEon was effective and well tolerated.

Dual Hypocretin Receptor Antagonism Is More Effective for Sleep Promotion than Antagonism of Either Receptor Alone

It is concluded that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either H CRTR alone.

Pharmacokinetics and Pharmacodynamics of the Dual Orexin Receptor Antagonist Daridorexant in Japanese and Caucasian Subjects.

Japanese showed slightly larger PD effects and reported more adverse events than Caucasians, and the PK, PD, and safety profile of daridorexant were similar in Japanese and Caucasian subjects.

Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism

Results indicate that additional blockade of OX1R to OX2R antagonism elicits a dysregulation of REM sleep by shifting the balance in favor ofREM sleep at the expense of NREM sleep that may increase the risk of adverse events.

Accelerated Development of the Dual Orexin Receptor Antagonist ACT‐541468: Integration of a Microtracer in a First‐in‐Human Study

Clear dose‐related effects on the central nervous system were observed at ≥25 mg, indicating a suitable PK‐PD profile for a sleep‐promoting drug, allowing for rapid onset and duration of action limited to the intended use.

Orexin receptor antagonism for treatment of insomnia

The data suggest that orexin receptor antagonism offers a novel approach to treating insomnia, and Class I evidence that suvorexant improves sleep efficiency over 4 weeks in nonelderly adult patients with primary insomnia.

A randomized Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with insomnia without psychiatric comorbidity

Investigation of the effect of seltorexant on sleep efficiency after single and multiple dose administration in subjects with insomnia disorder without psychiatric comorbidity resulted in a prolonged total sleep time, shorter latency to persistent sleep and wake after sleep onset.

Orexin Receptor Antagonism, a New Sleep-Enabling Paradigm: A Proof-of-Concept Clinical Trial

Almorexant consistently and dose‐dependently improved sleep variables and may offer a new treatment approach for primary insomnia.