Identification
- Summary
Lemborexant is a dual orexin antagonist indicated for the treatment of sleep-onset and/or sleep maintenance insomnia.
- Brand Names
- Dayvigo
- Generic Name
- Lemborexant
- DrugBank Accession Number
- DB11951
- Background
Lemborexant is a novel dual orexin receptor antagonist used in the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.5 Recent research in the field of sleep disorders has revealed that insomnia is likely driven not by the inability of the brain to "switch on" sleep-related circuits, but rather an inability to "switch-off" wake-promoting circuits.3,4 Whereas historically popular pharmacologic treatments for insomnia (e.g. zopiclone, zolpidem, benzodiazepines) focus on enhancing sleep drive via modulation of GABA and melatonin receptors, lemborexant and other orexin antagonists (e.g. suvorexant) act to counteract inappropriate wakefulness.3 This novel mechanism of action offers potential advantages over classic hypnotic agents, including a more favorable adverse effect profile and potentially greater efficacy, and may signal the beginning of a new wave of treatment options for patients suffering from insomnia.3
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Lemborexant (DB11951)
- Weight
- Average: 410.425
Monoisotopic: 410.155432226 - Chemical Formula
- C22H20F2N4O2
- Synonyms
- Lemborexant
- External IDs
- E 2006
- E-2006
- E2006
Pharmacology
- Indication
Lemborexant is indicated for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.5
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Insomnia •••••••••••• ••••• •••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Lemborexant promotes sleep by antagonizing the actions of wake-promoting chemicals in the brain.5 Episodes of complex sleep behaviors (e.g. eating food, having sex, making phone calls) have been reported in patients using lemborexant - these events may occur in hypnotic-naive and hyponotic-experienced patients, and patients are unlikely to remember these events. Patients exhibiting complex sleep behaviors should discontinue lemborexant immediately. Lemborexant may carry some risk of abuse, and should be used with caution in patients with a history of alcohol or drug addiction. Its controlled substance schedule is currently under review by the Drug Enforcement Administration.5
- Mechanism of action
The orexin neuropeptide signaling system is involved in many physiologic functions, including sleep/wake control. Orexin-A and orexin-B activate post-synaptic G-protein coupled2 orexin-1 receptors (OX1R) and orexin-2 receptors (OX2R), which are found on neurons in the hypothalamus that project to numerous wake-controlling nuclei. Each receptor carries slightly different activity - activation of OX1R appears to suppress the onset of rapid eye movement (REM) sleep, whereas activation of OX2R appears to suppress non-REM sleep.3
Lemborexant is an competitive antagonist of OX1R and OX2R. By blocking the binding of wake-promoting orexin-A and -B at these receptors, lemborexant suppresses the wake-drive, thereby promoting sleep.5
Target Actions Organism AOrexin receptor type 1 antagonistHumans AOrexin receptor type 2 antagonistHumans - Absorption
Animal models of lemborexant disposition have demonstrated rapid absorption following oral administration.2 The Tmax of lemborexant is approximately 1-3 hours, or 3-5 hours following administration of a high-fat, high-calorie meal.5 Cmax and AUC0-24h increase at a rate slightly less than proportionate to the given dose. Following administration of a high-fat, high-calorie meal, Cmax is decreased by 23% and AUC0-inf is increased by 18%.5 AUC, Cmax, and terminal half-life are increased in the presence of moderate hepatic impairment, and AUC (but not half-life) is increased in the presence of mild hepatic impairment.5
- Volume of distribution
The volume of distribution of lemborexant is 1970 L, indicating extensive tissue distribution.5
- Protein binding
Lemborexant is approximately 94% protein-bound in vitro, though the specific proteins to which it binds in plasma have not been elucidated.5
- Metabolism
Given that less than 1% of an administered dose is recovered unchanged in the urine,5 it is likely that lemborexant is extensively metabolized - this has been confirmed in rat and monkey models,2 but its metabolism in humans has not been fully characterized. Prescribing information states that it is predominantly metabolized by CYP3A4, with a smaller contribution by CYP3A5. The major circulating metabolite is lemborexant's M10 metabolite, which is pharmacologically active and binds to orexin receptors with a similar affinity to the parent drug. The M10 metabolite has the potential to induce CYP3A and CYP2B6 enzymes, weakly inhibit CYP3A enzymes, and is a substrate of P-gp transporters.5
- Route of elimination
Following oral administration, 57.4% of the dose is found in the feces and 29.1% in the urine. Less than 1% of the dose recovered in the urine exists as unchanged parent drug, suggesting extensive metabolism.5
- Half-life
The half-life for lemborexant at doses of 5mg and 10mg is 17 and 19 hours, respectively.5
- Clearance
Not Available
- Adverse Effects
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Clinical experience with lemborexant overdose is limited. In clinical studies, healthy patients receiving doses up to 10x the recommended maximum dose experienced dose-dependent increases in the frequency of adverse effects such as somnolence - it is likely, then, that symptoms of overdose will be consistent with lemborexant's adverse effect profile.5 In the event of an overdosage, implement supportive measures and consult the nearest poison control center for the most up to date management strategies. As lemborexant is highly protein-bound, hemodialysis is likely to be of little use in overdose situations.5
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of CNS depression can be increased when Lemborexant is combined with 1,2-Benzodiazepine. Abametapir The serum concentration of Lemborexant can be increased when it is combined with Abametapir. Abatacept The metabolism of Lemborexant can be increased when combined with Abatacept. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Lemborexant. Abrocitinib The serum concentration of Lemborexant can be increased when it is combined with Abrocitinib. - Food Interactions
- Take on an empty stomach. Co-administration with food delays absorption and sleep onset.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Dayvigo Tablet, film coated 10 mg/1 Oral Eisai Inc. 2020-04-07 Not applicable US 
Dayvigo Tablet 10 mg Oral Eisai Limited 2020-11-06 Not applicable Canada 
Dayvigo Tablet, film coated 5 mg/1 Oral Eisai Inc. 2020-04-07 Not applicable US Dayvigo Tablet, film coated 5 mg/1 Oral Eisai Inc. 2020-04-07 2023-02-28 US Dayvigo Tablet 5 mg Oral Eisai Limited 2020-11-06 Not applicable Canada
Categories
- ATC Codes
- N05CM21 — Lemborexant
- Drug Categories
- Central Nervous System Agents
- Central Nervous System Depressants
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2B6 Inducers (strength unknown)
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Hypnotics and Sedatives
- Nervous System
- Neurotransmitter Agents
- Orexin Receptor Antagonists
- P-glycoprotein substrates
- Psycholeptics
- Sleep Aids, Pharmaceutical
- Sleep Initiation and Maintenance Disorders
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as n-arylamides. These are organic compounds that contain a carboxamide group that is N-linked to a aryl group. They have the generic structure RC(=O)N(R')H, R = organyl group and R'= aryl group.
- Kingdom
- Organic compounds
- Super Class
- Organic nitrogen compounds
- Class
- Organonitrogen compounds
- Sub Class
- N-arylamides
- Direct Parent
- N-arylamides
- Alternative Parents
- Fluorobenzenes / Alkyl aryl ethers / Pyrimidines and pyrimidine derivatives / Pyridines and derivatives / Imidolactams / Cyclopropanecarboxylic acids and derivatives / Aryl fluorides / Heteroaromatic compounds / Secondary carboxylic acid amides / Azacyclic compounds show 4 more
- Substituents
- Alkyl aryl ether / Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Cyclopropanecarboxylic acid or derivatives show 17 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 0K5743G68X
- CAS number
- 1369764-02-2
- InChI Key
- MUGXRYIUWFITCP-PGRDOPGGSA-N
- InChI
- 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
- IUPAC Name
- (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide
- SMILES
- CC1=NC=C(OC[C@]2(C[C@H]2C(=O)NC2=NC=C(F)C=C2)C2=CC=CC(F)=C2)C(C)=N1
References
- Synthesis Reference
Yoshida, Y. et. al. "Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist," J. Med. Chem. 2015, 58, 11, 4648-4664.
- General References
- Mahoney CE, Mochizuki T, Scammell TE: Dual orexin receptor antagonists increase sleep and cataplexy in wild type mice. Sleep. 2019 Dec 13. pii: 5674930. doi: 10.1093/sleep/zsz302. [Article]
- Ueno T, Ishida T, Kusano K: Disposition and metabolism of [(14)C]lemborexant, a novel dual orexin receptor antagonist, in rats and monkeys. Xenobiotica. 2019 Jun;49(6):688-697. doi: 10.1080/00498254.2018.1482509. Epub 2018 Jul 5. [Article]
- Beuckmann CT, Suzuki M, Ueno T, Nagaoka K, Arai T, Higashiyama H: In Vitro and In Silico Characterization of Lemborexant (E2006), a Novel Dual Orexin Receptor Antagonist. J Pharmacol Exp Ther. 2017 Aug;362(2):287-295. doi: 10.1124/jpet.117.241422. Epub 2017 May 30. [Article]
- Beuckmann CT, Ueno T, Nakagawa M, Suzuki M, Akasofu S: Preclinical in vivo characterization of lemborexant (E2006), a novel dual orexin receptor antagonist for sleep/wake regulation. Sleep. 2019 Jun 11;42(6). pii: 5421821. doi: 10.1093/sleep/zsz076. [Article]
- FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]
- Carbosynth: Lemborexant MSDS [Link]
- External Links
- PubChem Compound
- 56944144
- PubChem Substance
- 347828277
- ChemSpider
- 34500836
- BindingDB
- 50093793
- 2272403
- ChEMBL
- CHEMBL3545367
- ZINC
- ZINC000118073503
- PDBe Ligand
- NRK
- Wikipedia
- Lemborexant
- PDB Entries
- 6tot / 7xrr
- FDA label
- Download (586 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Treatment Insomnia 1 4 Not Yet Recruiting Treatment Dementia / Frontal Temporal Dementia (FTD) / Insomnia 1 4 Recruiting Treatment Delayed Sleep Phase Syndrome 1 4 Recruiting Treatment Shift-work related sleep disturbance 1 3 Completed Treatment Insomnia 2
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 10 mg Tablet Oral 5 mg Tablet Oral 5.000 mg Tablet, film coated Oral 10 mg/1 Tablet, film coated Oral 5 mg/1 Tablet, film coated Oral 5 MG Tablet, film coated Oral 10 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8268848 No 2012-09-18 2031-09-20 US US10188652 No 2019-01-29 2035-10-21 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0111 mg/mL ALOGPS logP 3.39 ALOGPS logP 3.34 Chemaxon logS -4.6 ALOGPS pKa (Strongest Acidic) 12.12 Chemaxon pKa (Strongest Basic) 3.15 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 77 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 107.94 m3·mol-1 Chemaxon Polarizability 40.54 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-03dj-0090600000-946514e0ba08b69360f6 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-05g0-0943300000-b29c4eb1bf349a36c207 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-03di-0433900000-3f26ad13c1a15e7cdf46 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-000b-1921000000-d2b2faffa4e33c6f7dd3 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0089-0659100000-f18466e7b64d0b353faa Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-008i-2933000000-808e94cc9e6e082223a4 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 192.3661 predictedDeepCCS 1.0 (2019) [M+H]+ 194.76169 predictedDeepCCS 1.0 (2019) [M+Na]+ 200.67421 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Peptide hormone binding
- Specific Function
- Moderately selective excitatory receptor for orexin-A and, with a lower affinity, for orexin-B neuropeptide. Seems to be exclusively coupled to the G(q) subclass of heteromeric G proteins, which ac...
- Gene Name
- HCRTR1
- Uniprot ID
- O43613
- Uniprot Name
- Orexin receptor type 1
- Molecular Weight
- 47535.33 Da
References
- FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Peptide hormone binding
- Specific Function
- Nonselective, high-affinity receptor for both orexin-A and orexin-B neuropeptides.
- Gene Name
- HCRTR2
- Uniprot ID
- O43614
- Uniprot Name
- Orexin receptor type 2
- Molecular Weight
- 50693.965 Da
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Oxygen binding
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- InhibitorInducer
- Curator comments
- From Dayvigo prescribing information: "...lemborexant and M10 have the potential to induce CYP3A and the weak potential to inhibit CYP3A...". The extent of each is unclear.
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Components:
| Name | UniProt ID |
|---|---|
| Cytochrome P450 3A4 | P08684 |
| Cytochrome P450 3A43 | Q9HB55 |
| Cytochrome P450 3A5 | P20815 |
| Cytochrome P450 3A7 | P24462 |
References
- FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]
Drug created at October 20, 2016 21:04 / Updated at April 01, 2022 20:23