Lemborexant

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Lemborexant
Clinical data
Trade namesDayvigo
Other namesE-2006
License data
Pregnancy
category
Routes of
administration		By mouth[3]
Drug classOrexin receptor antagonist; Hypnotic; Sedative
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityGood (≥87%)[5][6]
Protein binding94%[3]
MetabolismLiver (major: CYP3A4, minor: CYP3A5)[3]
MetabolitesM10[3]
Elimination half-life17–19 hours or 55 hours[3][7]
ExcretionFeces: 57.4%[3]
Urine: 29.1%[3]
Identifiers
  • (1R,2S)-2-[(2,4-Dimethylpyrimidin-5-yl)oxymethyl]-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
E number{{#property:P628}}
CompTox Dashboard (EPA)
  • {{#property:P3117}}Lua error in Module:EditAtWikidata at line 29: attempt to index field 'wikibase' (a nil value).
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Chemical and physical data
FormulaC22H20F2N4O2
Molar mass410.425 g·mol−1
3D model (JSmol)
  • CC1=NC(=NC=C1OC[C@]2(C[C@H]2C(=O)NC3=NC=C(C=C3)F)C4=CC(=CC=C4)F)C
  • InChI=1S/C22H20F2N4O2/c1-13-19(11-25-14(2)27-13)30-12-22(15-4-3-5-16(23)8-15)9-18(22)21(29)28-20-7-6-17(24)10-26-20/h3-8,10-11,18H,9,12H2,1-2H3,(H,26,28,29)/t18-,22+/m0/s1
  • Key:MUGXRYIUWFITCP-PGRDOPGGSA-N

Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia.[3][8] It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maintenance in adults.[3][8] The medication is taken by mouth.[3][8]

Side effects of lemborexant include somnolence, fatigue, headache, and abnormal dreams.[3][8] The medication is a dual orexin receptor antagonist (DORA).[3][8] It acts as a selective dual antagonist of the orexin receptors OX1 and OX2.[3][8] Lemborexant has a long elimination half-life of 17 to 55 hours and a time to peak of about 1 to 3 hours.[3][8] It is not a benzodiazepine or Z-drug and does not interact with GABA receptors, instead having a distinct mechanism of action.[3][8]

Lemborexant was approved for medical use in the United States in December 2019.[9][10][11] It is a schedule IV controlled substance in the United States and may have a low potential for misuse.[3][8] Besides lemborexant, other orexin receptor antagonists including suvorexant and daridorexant have also been introduced.[12][13]

Medical uses

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Lemborexant is used in the treatment of insomnia in adults.[3]

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 weeks of 0.36 (95% CITooltip confidence interval 0.08 to 0.63) and at 3 months of 0.41 (95% CI 0.04 to 0.78).[14] Lemborexant had similar effect sizes at 4 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.[14] 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.[14]

Compared to benzodiazepines, there is a low risk of developing tolerance and dependence.[15] Memory and attention are not affected the next morning when taking lemborexant.[16]

Available forms

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Lemborexant is available in the form of 5 and 10 mg oral film-coated tablets.[3]

Side effects

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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).[3] 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).[3]

Lemborexant at doses of 10, 20, and 30 mg produces drug-liking responses similar to those of zolpidem (30 mg) and suvorexant (40 mg) in recreational sedative drug users.[3] It is a controlled substance in the United States and is considered to have a low misuse potential.[3][17]

Pharmacology

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Pharmacodynamics

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Lemborexant is a dual antagonist of the orexin OX1 and OX2 receptors.[18][19][20] 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.[12]

Pharmacokinetics

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The bioavailability of lemborexant is good and is at least 87%.[5][6] The time to peak levels of lemborexant is 1 to 3 hours.[3] A high-fat and high-calorie meal has been found to delay the time to peak levels by 2 hours.[3] Its plasma protein binding in vitro is 94%.[3] Lemborexant is metabolized primarily by CYP3A4 and to a lesser extent by CYP3A5.[3] The "effective" half-life of lemborexant is 17 to 19 hours while its terminal elimination half-life is 55 hours.[3][7][8] The medication is excreted in feces (57%) and to a lesser extent urine (29%).[3]

Peak-normalized concentrations (% of Cmax) of the orexin receptor antagonists suvorexant (SUV; 20 mg) and lemborexant (LEM; 10 mg) with administration at steady state in humans.[21]

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.[21][7] In addition, lemborexant dissociates from the orexin receptors more rapidly than does suvorexant.[21] These differences may allow for comparatively reduced next-day effects such as daytime somnolence with lemborexant.[21][7]

History

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In June 2016, Eisai initiated Phase III clinical trials in the United States, France, Germany, Italy, Japan, Poland, Spain and the UK.[22]

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.[11][23]

Society and culture

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Names

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Lemborexant is the generic name of the drug and its INNTooltip International Nonproprietary Name while E-2006 was its developmental code name. Lemborexant is sold under the brand name Dayvigo.[3]

Availability

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Lemborexant is marketed in the United States, Canada, Australia, and Japan.[24][25][26][27] 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.[28][29]

Research

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Lemborexant is under development for the treatment of circadian rhythm sleep disorders, sleep apnea, and chronic obstructive pulmonary disease.[30] 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.[30]

References

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