Identification

Summary

Daridorexant is a dual orexin receptor antagonist used to treat insomnia in adults.

Brand Names
Quviviq
Generic Name
Daridorexant
DrugBank Accession Number
DB15031
Background

Daridorexant, formerly known as nemorexant, is a selective dual orexin receptor antagonist used to treat insomnia. Insomnia is characterized by difficulties with sleep onset and/or sleep maintenance and impairment of daytime functioning. It chronically affects the person's daily functioning and long-term health effects, as insomnia is often associated with comorbidities such as hypertension, diabetes, and depression. Conventional treatments for insomnia include drugs targeting gamma-aminobutyric acid type-A (GABA-A), serotonin, histamine, or melatonin receptors; however, undesirable side effects are frequently reported, such as next-morning residual sleepiness, motor incoordination, falls, memory and cognitive impairment. Novel drugs that target orexin receptors gained increasing attention after discovering the role of orexin signalling pathway in wakefulness and almorexant, an orexin receptor antagonist that improved sleep. Daridorexant was designed via an intensive drug discovery program to improve the potency and maximize the duration of action while minimizing next-morning residual activity.1

Daridorexant works on orexin receptors OX1R and OX2R to block the binding of orexins, which are wake-promoting neuropeptides and endogenous ligands to these receptors. Daridorexant reduces overactive wakefulness: in the investigational trials, daridorexant reportedly improved sleep and daytime functioning in patients with insomnia.1 It was approved by the FDA on January 10, 2022, under the name QUVIVIQ.6 as the second orexin receptor antagonist approved to treat insomnia following suvorexant.2 Daridorexant was approved by the European Commission on May 3, 2022 as the first dual orexin receptor antagonist approved in the market.8

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 450.93
Monoisotopic: 450.1571017
Chemical Formula
C23H23ClN6O2
Synonyms
  • ACT-541468
  • Nemorexant

Pharmacology

Indication

In the US and Europe, daridorexant is indicated for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.5 The European prescribing information states that insomnia should be characterized by symptoms that are present for at least 3 months and considerable impact on daytime functioning.7

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Daridorexant binds to and antagonizes the orexin receptors OX1R and OX2R (Ki = 0.47 and 0.93 nM, respectively) equipotentally.5 In clinical trials, daridorexant improved sleep onset and sleep maintenance, and patient-reported total sleep time. Patient-reported daytime sleepiness was also reportedly reduced.6 At a dose four times the maximum recommended dose, daridorexant does not prolong the QTc interval to any clinically relevant extent.5

Daridorexant is currently being assessed for a controlled substance schedule in the US. In a human abuse potential study, daridorexant showed some abuse potential at doses higher than the recommended dose (100-150 mg), indicated by similar “drug liking” ratings to zolpidem (30 mg) and suvorexant in recreational sedative drug users.5 However, at clinically relevant concentrations, daridorexant does not bind to abuse-associated CNS targets.1 In animal studies and clinical trials evaluating physical dependence, chronic administration of daridorexant did not produce withdrawal signs or symptoms upon drug discontinuation, indicating that the drug does not produce physical dependence.5

Mechanism of action

The sleep and wake cycle is regulated by complex interactions between sleep-promoting systems, including inhibitory GABA activity, and wake-promoting systems, including orexins, acetylcholine and monoaminergic systems.2 Orexin, also called hypocretin, is a wake-promoting neuropeptide produced by a small group of neurons in the lateral hypothalamus.2 Orexin stabilizes wakefulness by activating orexin neurons with the highest activity during active wakefulness and minimal activity during sleep.1 Orexin neurons project to other wake-promoting neurons that also express orexin receptors: these include the histaminergic neurons of the tuberomammillary nucleus, noradrenergic neurons of the locus coeruleus, serotoninergic neurons of the dorsal raphe, dopaminergic neurons of the ventral tegmental area, and cholinergic neurons of the basal forebrain and the pedunculopontine and laterodorsal tegmental nuclei.1 These wake-promoting neurons are part of the ascending reticular activating system that operates under a feedback loop in the sleep and wake cycle.4

There are two identified types of orexin (OXA and OXB) that bind to orexin type 1 and 2 receptors (OX1R and OX2R), which are G-protein coupled receptors. OXA binds more preferentially to OX1R, while OX2R shows a dual affinity for OXA and OXB.4 The defined role of each orexin receptor is still unclear; however, there is some evidence suggesting that OX2R regulates sleep and wake, while OX1R have some role in sleep maintenance.2 Daridorexant blocks the binding of wake-promoting neuropeptides OXA and OXB to OX1R and OX2R, thereby suppressing wake drive.5 Daridorexant selectively targets orexin neurons and inhibits downstream neuronal pathways that promote wakefulness; however, it does not affect neuronal pathways that cause side effects commonly seen in positive allosteric GABA-A receptor modulators.1

TargetActionsOrganism
AOrexin receptor type 1
antagonist
Humans
AOrexin receptor type 2
antagonist
Humans
Absorption

Daridorexant reaches peak plasma concentrations within one to two hours. Daridorexant has an absolute bioavailability of 62%. While a high-fat and high-calorie meal delayed the Tmax by 1.3 hours and decreased the Cmax by 16% in healthy subjects, the total exposure (AUC) was not affected.5

Volume of distribution

Daridorexant has a volume of distribution of 31 L. The blood to plasma ratio is 0.64.5 It effectively passes the blood-brain barrier.1

Protein binding

Daridorexant is 99.7% bound to plasma proteins.5

Metabolism

Daridorexant undergoes extensive metabolism primarily mediated by CYP3A4 (89%),5 mostly via oxidative transformations.3 Other CYP enzymes individually contribute to less than 3% of metabolic clearance of daridorexant.5

Route of elimination

The primary route of excretion is via feces, accounting for approximately 57% of drug excretion. About 28% of the drug is excreted via urine primarily in the form of metabolites. Trace amounts of the parent drug were found in feces and urine.5

Half-life

The terminal half-life is approximately 8 hours.5

Clearance

There is limited information on clearance.

Adverse Effects
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Toxicity

There is limited clinical experience with daridorexant overdose. In clinical pharmacology studies, healthy subjects were administered single doses of up to 200 mg, four times the maximum recommended dose. Somnolence, muscle weakness, cataplexy-like symptoms, sleep paralysis, disturbance in attention, fatigue, headache, and constipation were observed in these patients.

There is no specific antidote to overdosage of daridorexant. In the event of an overdose, general symptomatic and supportive medical care, along with immediate gastric lavage where appropriate, should be provided in addition to careful monitoring. Dialysis is unlikely to be effective as daridorexant is highly protein-bound.5

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of CNS depression can be increased when 1,2-Benzodiazepine is combined with Daridorexant.
AbametapirThe serum concentration of Daridorexant can be increased when it is combined with Abametapir.
AcetazolamideThe risk or severity of CNS depression can be increased when Acetazolamide is combined with Daridorexant.
AcetophenazineThe risk or severity of CNS depression can be increased when Acetophenazine is combined with Daridorexant.
AclidiniumDaridorexant may increase the central nervous system depressant (CNS depressant) activities of Aclidinium.
AgomelatineThe risk or severity of CNS depression can be increased when Agomelatine is combined with Daridorexant.
AlfentanilThe risk or severity of CNS depression can be increased when Alfentanil is combined with Daridorexant.
AlimemazineThe risk or severity of CNS depression can be increased when Alimemazine is combined with Daridorexant.
AlmotriptanThe risk or severity of CNS depression can be increased when Almotriptan is combined with Daridorexant.
AlosetronThe risk or severity of CNS depression can be increased when Alosetron is combined with Daridorexant.
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Food Interactions
  • Avoid alcohol. Concomitant use of alcohol with daridorexant may lead to additive impairment of psychomotor performance and risk of CNS depression .

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
QuviviqTablet, film coated25 mg/1OralIdorsia Pharmaceuticals Ltd2022-04-07Not applicableUS flag
QuviviqTablet, film coated25 mgOralIdorsia Pharmaceuticals Deutschland Gmb H2022-06-13Not applicableEU flag
QuviviqTablet, film coated25 mgOralIdorsia Pharmaceuticals Deutschland Gmb H2022-05-04Not applicableEU flag
QuviviqTablet, film coated50 mgOralIdorsia Pharmaceuticals Deutschland Gmb H2022-05-04Not applicableEU flag
QuviviqTablet, film coated50 mg/1OralIdorsia Pharmaceuticals Ltd2022-04-07Not applicableUS flag
QuviviqTablet, film coated50 mgOralIdorsia Pharmaceuticals Deutschland Gmb H2022-06-13Not applicableEU flag
QuviviqTablet, film coated25 mgOralIdorsia Pharmaceuticals Deutschland Gmb H2022-05-04Not applicableEU flag
QuviviqTablet, film coated50 mgOralIdorsia Pharmaceuticals Deutschland Gmb H2022-05-04Not applicableEU flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
LMQ24G57E9
CAS number
1505484-82-1
InChI Key
NBGABHGMJVIVBW-QHCPKHFHSA-N
InChI
InChI=1S/C23H23ClN6O2/c1-14-17(24)6-7-18-20(14)28-22(27-18)23(2)9-4-12-29(23)21(31)16-13-15(32-3)5-8-19(16)30-25-10-11-26-30/h5-8,10-11,13H,4,9,12H2,1-3H3,(H,27,28)/t23-/m0/s1
IUPAC Name
5-chloro-2-[(2S)-1-[5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl]-2-methylpyrrolidin-2-yl]-4-methyl-1H-1,3-benzodiazole
SMILES
COC1=CC(C(=O)N2CCC[C@@]2(C)C2=NC3=C(N2)C=CC(Cl)=C3C)=C(C=C1)N1N=CC=N1

References

General References
  1. Roch C, Bergamini G, Steiner MA, Clozel M: Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia. Psychopharmacology (Berl). 2021 Oct;238(10):2693-2708. doi: 10.1007/s00213-021-05954-0. Epub 2021 Aug 20. [Article]
  2. Herring WJ, Roth T, Krystal AD, Michelson D: Orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications. J Sleep Res. 2019 Apr;28(2):e12782. doi: 10.1111/jsr.12782. Epub 2018 Oct 18. [Article]
  3. Muehlan C, Fischer H, Zimmer D, Aissaoui H, Grimont J, Boss C, Croft M, van Gerven J, Krahenbuhl S, Dingemanse J: Metabolism of the Dual Orexin Receptor Antagonist ACT-541468, Based on Microtracer/ Accelerator Mass Spectrometry. Curr Drug Metab. 2019;20(4):254-265. doi: 10.2174/1389200220666190206141814. [Article]
  4. Janto K, Prichard JR, Pusalavidyasagar S: An Update on Dual Orexin Receptor Antagonists and Their Potential Role in Insomnia Therapeutics. J Clin Sleep Med. 2018 Aug 15;14(8):1399-1408. doi: 10.5664/jcsm.7282. [Article]
  5. FDA Approved Drug Products: QUVIVIQ (daridorexant) tablets, for oral use [Link]
  6. Idorsia News: Idorsia receives US FDA approval of QUVIVIQ (daridorexant) 25 and 50 mg for the treatment of adults with insomnia [Link]
  7. EMA Approved Drug Products: Quviviq (daridorexant) Oral Tablets [Link]
  8. GlobeNewswire News Release: Europe’s first dual orexin receptor antagonist – QUVIVIQ (daridorexant) – granted approval to improve both nighttime symptoms and daytime functioning in adults with chronic insomnia disorder [Link]
ChemSpider
64854514
BindingDB
334973
RxNav
2591497
ChEMBL
CHEMBL4297590
PDBe Ligand
NS2
Wikipedia
Daridorexant
PDB Entries
6tp3

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentInsomnia Disorder3
2CompletedTreatmentInsomnia Disorder2
1CompletedOtherHealthy Subjects (HS)10
1CompletedOtherHealthy Subjects (HS) / Impaired Renal Function1
1CompletedOtherHepatic Impairment1
1CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1
1CompletedTreatmentHealthy Recreational Drug Users1
1CompletedTreatmentHealthy Subjects (HS)1
1CompletedTreatmentObstructive Sleep Apnea (OSA)1
1Not Yet RecruitingTreatmentHepatic Impairment1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral25 mg
Tablet, film coatedOral25 mg/1
Tablet, film coatedOral50 mg
Tablet, film coatedOral50 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9732075No2013-06-122033-06-12US flag
US10023560No2014-12-022034-12-02US flag
US9790208No2014-12-022034-12-02US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0112 mg/mLALOGPS
logP3.73ALOGPS
logP3.04ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)11.8ChemAxon
pKa (Strongest Basic)5.06ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area88.93 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity133.7 m3·mol-1ChemAxon
Polarizability45.6 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
Curator comments
According to the US prescribing information, the inhibitory constant (Ki) is 0.47 nM.
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
  1. Roch C, Bergamini G, Steiner MA, Clozel M: Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia. Psychopharmacology (Berl). 2021 Oct;238(10):2693-2708. doi: 10.1007/s00213-021-05954-0. Epub 2021 Aug 20. [Article]
  2. FDA Approved Drug Products: QUVIVIQ (daridorexant) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
Curator comments
According to the US prescribing information, the inhibitory constant (Ki) is 0.93 nM.
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
References
  1. Roch C, Bergamini G, Steiner MA, Clozel M: Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia. Psychopharmacology (Berl). 2021 Oct;238(10):2693-2708. doi: 10.1007/s00213-021-05954-0. Epub 2021 Aug 20. [Article]
  2. FDA Approved Drug Products: QUVIVIQ (daridorexant) tablets, for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
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
  1. FDA Approved Drug Products: QUVIVIQ (daridorexant) tablets, for oral use [Link]

Drug created at May 20, 2019 14:43 / Updated at June 01, 2022 17:06