Lemborexant

Lemborexant is used in the treatment of insomnia in adults.

A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found that lemborexant had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4{{nbsp}}weeks of 0.36 (95% {{Abbrlink|CI|confidence interval}} 0.08 to 0.63) and at 3{{nbsp}}months of 0.41 (95% {{Abbr|CI|confidence interval}} 0.04 to 0.78).{{cite journal | vauthors = De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Kurtulmus A, Tomlinson A, Mitrova Z, Foti F, Del Giovane C, Quested DJ, Cowen PJ, Barbui C, Amato L, Efthimiou O, Cipriani A | title = Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis | journal = Lancet | volume = 400 | issue = 10347 | pages = 170–184 | date = July 2022 | pmid = 35843245 | doi = 10.1016/S0140-6736(22)00878-9 | s2cid = 250536370 | url = | doi-access = free | hdl = 11380/1288245 | hdl-access = free }} Lemborexant had similar effect sizes at 4{{nbsp}}weeks as the other evaluated and marketed orexin receptor antagonists suvorexant (SMD 0.31, 95% CI 0.01 to 0.62) and daridorexant (SMD 0.23, 95% CI –0.01 to 0.48), whereas benzodiazepines and Z-drugs generally showed larger effect sizes (e.g., SMDs of 0.45 to 0.83) than lemborexant and the other orexin receptor antagonists. However, the review concluded that lemborexant and eszopiclone among all of the insomnia medications assessed had the best profiles overall in terms of efficacy, tolerability, and acceptability.

Compared to benzodiazepines, there is a low risk of developing tolerance and dependence.{{cite journal | vauthors = Suzuki H, Hibino H | title = The effect of lemborexant for insomnia disorder | journal = SAGE Open Medicine | volume = 9 | pages = 20503121211039098 | date = 18 August 2021 | pmid = 34422270 | pmc = 8377315 | doi = 10.1177/20503121211039098 }} Memory and attention are not affected the next morning when taking lemborexant.{{cite journal | vauthors = Murphy P, Kumar D, Zammit G, Rosenberg R, Moline M | title = Safety of lemborexant versus placebo and zolpidem: effects on auditory awakening threshold, postural stability, and cognitive performance in healthy older participants in the middle of the night and upon morning awakening | journal = Journal of Clinical Sleep Medicine | volume = 16 | issue = 5 | pages = 765–773 | date = May 2020 | pmid = 32022664 | pmc = 7849806 | doi = 10.5664/jcsm.8294 }}

Lemborexant is available in the form of 5 and 10{{nbsp}}mg oral film-coated tablets.

Side effects of lemborexant include somnolence or fatigue (combined preferred terms of somnolence, lethargy, fatigue, and sluggishness) (6.9% at 5 mg and 9.6% at 10 mg vs. 1.3% for placebo), headache (5.9% at 5 mg and 4.5% at 10 mg vs. 3.4% for placebo), and nightmares or abnormal dreams (0.9% at 5 mg and 2.2% at 10 mg vs. 0.9% for placebo). Less common side effects include sleep paralysis (1.3% at 5 mg and 1.6% at 10 mg vs. 0% for placebo) and hypnagogic hallucinations (0.1% at 5 mg and 0.7% at 10 mg vs. 0% for placebo).

Lemborexant at doses of 10, 20, and 30{{nbsp}}mg produces drug-liking responses similar to those of zolpidem (30{{nbsp}}mg) and suvorexant (40{{nbsp}}mg) in recreational sedative drug users. It is a controlled substance in the United States and is considered to have a low misuse potential.{{cite journal | vauthors = Asakura S, Shiotani M, Gauvin DV, Fujiwara A, Ueno T, Bower N, Beuckmann CT, Moline M | title = Nonclinical evaluation of abuse liability of the dual orexin receptor antagonist lemborexant | journal = Regulatory Toxicology and Pharmacology | volume = 127 | issue = | pages = 105053 | date = December 2021 | pmid = 34619288 | doi = 10.1016/j.yrtph.2021.105053 | s2cid = 238476630 | doi-access = free }}

Lemborexant is a dual antagonist of the orexin OX₁ and OX₂ receptors.{{cite journal | vauthors = Christopher JA | title = Small-molecule antagonists of the orexin receptors | journal = Pharmaceutical Patent Analyst | volume = 3 | issue = 6 | pages = 625–638 | year = 2014 | pmid = 25489915 | doi = 10.4155/ppa.14.46 }}{{cite journal | vauthors = Boss C, Roch C | title = Recent trends in orexin research--2010 to 2015 | journal = Bioorganic & Medicinal Chemistry Letters | volume = 25 | issue = 15 | pages = 2875–2887 | date = August 2015 | pmid = 26045032 | doi = 10.1016/j.bmcl.2015.05.012 }}{{cite journal | vauthors = Boss C | title = Orexin receptor antagonists--a patent review (2010 to August 2014) | journal = Expert Opinion on Therapeutic Patents | volume = 24 | issue = 12 | pages = 1367–1381 | date = December 2014 | pmid = 25407283 | doi = 10.1517/13543776.2014.978859 | s2cid = 21106711 }} It associates and dissociates from the orexin receptors more rapidly than certain other orexin receptor antagonists, such as suvorexant, and this may cause it to have a shorter duration of action.{{cite journal | vauthors = Jacobson LH, Hoyer D, de Lecea L | title = Hypocretins (orexins): The ultimate translational neuropeptides | journal = Journal of Internal Medicine | volume = 291 | issue = 5 | pages = 533–556 | date = May 2022 | pmid = 35043499 | doi = 10.1111/joim.13406 | s2cid = 248119793 }}

The bioavailability of lemborexant is good and is at least 87%.{{cite journal | vauthors = Hoyer D, Jacobson LH | title = Lemborexant. Dual orexin receptor antagonist, Treatment of insomnia | journal = Drugs of the Future | date = 2018 | volume = 43 | issue = 10 | page = 715 | issn = 0377-8282 | doi = 10.1358/dof.2018.043.10.2828699 | pmid = | url = }}{{cite journal | vauthors = Lalovic B, Majid O, Aluri J, Landry I, Moline M, Hussein Z | title = Population Pharmacokinetics and Exposure-Response Analyses for the Most Frequent Adverse Events Following Treatment With Lemborexant, an Orexin Receptor Antagonist, in Subjects With Insomnia Disorder | journal = Journal of Clinical Pharmacology | volume = 60 | issue = 12 | pages = 1642–1654 | date = December 2020 | pmid = 32666570 | pmc = 7689791 | doi = 10.1002/jcph.1683 }} The time to peak levels of lemborexant is 1 to 3 hours. A high-fat and high-calorie meal has been found to delay the time to peak levels by 2 hours. Its plasma protein binding in vitro is 94%. Lemborexant is metabolized primarily by CYP3A4 and to a lesser extent by CYP3A5. The "effective" half-life of lemborexant is 17 to 19 hours while its terminal elimination half-life is 55 hours. The medication is excreted in feces (57%) and to a lesser extent urine (29%).

File:Peak normalized-concentrations of suvorexant and lemborexant with administration at steady state in humans.png) of the orexin receptor antagonists suvorexant (SUV; 20{{nbsp}}mg) and lemborexant (LEM; 10{{nbsp}}mg) with administration at steady state in humans.{{cite journal | vauthors = Kishi T, Nishida M, Koebis M, Taninaga T, Muramoto K, Kubota N, Moline M, Sakuma K, Okuya M, Nomura I, Iwata N | title = Evidence-based insomnia treatment strategy using novel orexin antagonists: A review | journal = Neuropsychopharmacology Reports | volume = 41 | issue = 4 | pages = 450–458 | date = December 2021 | pmid = 34553844 | pmc = 8698673 | doi = 10.1002/npr2.12205 }}]]

Although lemborexant has a longer terminal elimination half-life than suvorexant, it appears to be more rapidly cleared than suvorexant in the earlier phases of elimination.{{cite journal | vauthors = Muehlan C, Vaillant C, Zenklusen I, Kraehenbuehl S, Dingemanse J | title = Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 16 | issue = 11 | pages = 1063–1078 | date = November 2020 | pmid = 32901578 | doi = 10.1080/17425255.2020.1817380 | s2cid = 221572078 }} In addition, lemborexant dissociates from the orexin receptors more rapidly than does suvorexant. These differences may allow for comparatively reduced next-day effects such as daytime somnolence with lemborexant.

In June 2016, Eisai initiated Phase III clinical trials in the United States, France, Germany, Italy, Japan, Poland, Spain and the UK.{{cite web|url=https://www.sps.nhs.uk/medicines/lemborexant/|title=Lemborexant|website=Specialist Pharmacy Service|access-date=5 November 2017|archive-url=https://web.archive.org/web/20171107022108/https://www.sps.nhs.uk/medicines/lemborexant/|archive-date=7 November 2017|url-status=dead}}

In December 2019, lemborexant was approved for use in the United States based on results from the SUNRISE 1 and SUNRISE 2 Phase III clinical trials.{{cite web | title=FDA Approves Dayvigo (lemborexant) for the Treatment of Insomnia in Adult Patients | website=Drugs.com | date=23 December 2019 | url=https://www.drugs.com/newdrugs/fda-approves-dayvigo-lemborexant-insomnia-adult-patients-5132.html | access-date=10 January 2020}}{{cite web | title=Drug Trials Snapshot: Dayvigo | website=U.S. Food and Drug Administration (FDA) | date=20 December 2019 | url=http://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-dayvigo | access-date=24 January 2020}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}} {{PD-notice}}

Lemborexant is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}} while E-2006 was its developmental code name. Lemborexant is sold under the brand name Dayvigo.

Lemborexant is marketed in the United States, Canada, Australia, and Japan.{{cite web|url=https://www.micromedexsolutions.com/micromedex2/librarian/|title = Micromedex Products: Please Login}}{{cite web|url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html|title = Drug Product Database: Access the database|date = 18 March 2010}}{{cite web|url=https://www.tga.gov.au/apm-summary/dayvigo|title=Dayvigo|date=23 July 2021}}{{cite web|url=https://www.eisai.com/news/2020/news202036.html|title = EISAI TO LAUNCH IN-HOUSE DEVELOPED NEW ANTI-INSOMNIA DRUG DAYVIGO® (LEMBOREXANT) WITH INDICATION FOR INSOMNIA IN JAPAN | News Release：2020 | Eisai Co., Ltd}} It is not approved by the European Medicines Agency (EMA) for use in the European Union or by the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom.{{cite web | title = Medicines | work = European Medicines Agency | url = https://www.ema.europa.eu/en/medicines}}{{cite web | title = Products | work = Medicines and Healthcare products Regulatory Agency (MHRA) | url = https://products.mhra.gov.uk/}}

Lemborexant is under development for the treatment of circadian rhythm sleep disorders, sleep apnea, and chronic obstructive pulmonary disease.{{cite web|url=https://adisinsight.springer.com/drugs/800035210|title=Lemborexant - Eisai - AdisInsight}} As of February 2022, it is in phase 2 clinical trials for circadian rhythm sleep disorders and phase 1 trials for sleep apnea and chronic obstructive pulmonary disease.

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{{Hypnotics and sedatives}}

{{Insomnia pharmacotherapies}}

{{Orexin receptor modulators}}

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Category:Carboxamides

Category:Cyclopropanes

Category:3-Fluorophenyl compounds

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Category:Japanese inventions

Category:Orexin antagonists

Category:Organofluorides

Category:Pyrimidines

Category:Pyridines