Wikipedia

Daridorexant

Daridorexant,sold under the brand nameQuviviq,is anorexin antagonistmedicationwhich is used for the treatment ofinsomnia.[1][4][6][7][8]Daridorexant is takenby mouth.[1][4][7]

Daridorexant
Clinical data
Trade namesQuviviq
Other namesNemorexant; ACT-541468, Daridorexant hydrochloride (USANUS)
License data
Routes of
administration		By mouth[1]
Drug classDual orexin receptor antagonist;Hypnotic;Sedative
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability62%[1]
Protein binding99.7%[1]
MetabolismExtensive (mainlyCYP3A4(89%))[1]
Onset of actionTmax:1–2 hours (delayed by 1.3 hours with food)[1]
Eliminationhalf-life8 hours (6–10 hours)[1][5]
Duration of action~8 hours (50 mg)[5]
ExcretionFeces:~57%[1]
Urine:~28%[1]
Identifiers
  • [(2S)-2-(5-Chloro-4-methyl-1H-benzimidazol-2-yl)-2-methylpyrrolidin-1-yl]-[5-methoxy-2-(triazol-2-yl)phenyl]methanone
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard(EPA)
ECHA InfoCard100.353.123Edit this at Wikidata
Chemical and physical data
FormulaC23H23ClN6O2
Molar mass450.93g·mol−1
3D model (JSmol)
  • CC1=C(C=CC2=C1N=C(N2)[C@@]3(CCCN3C(=O)C4=C(C=CC(=C4)OC)N5N=CC=N5)C)Cl
  • 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
  • Key:NBGABHGMJVIVBW-QHCPKHFHSA-N

Side effectsof daridorexant includeheadache,somnolence,andfatigue.[1][7]The medication is adual orexin receptor antagonist(DORA).[9][7][10][8]It acts as aselectivedualantagonistof theorexin receptorsOX1andOX2.[9][10][8]Daridorexant has a relatively shortelimination half-lifeof 8hours and atime to peakof about 1 to 2hours.[1][7][5]It is not abenzodiazepineorZ-drugand does not interact withGABA receptors,instead having a distinctmechanism of action.[8][7]

Daridorexant was approved for medical use in the United States in January 2022[1][11]and became available in May 2022.[12]It was approved in the European Union in April 2022, and is the first orexin receptor antagonist to become available in European Union.[13]The medication is aschedule IVcontrolled substancein the United States and may have a modestpotential for misuse.[1][14][15]Besides daridorexant, other orexin receptor antagonists, likesuvorexantandlemborexant,have also been introduced.[16][17]

Medical uses

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Daridorexant isindicatedfor the treatment of adults withinsomniacharacterized by difficulties withsleep onsetand/orsleep maintenance.[1]The medication has been found to significantly improvelatency to persistent sleep(LPS),wake after sleep onset(WASO), and subjectivetotal sleep time(TST) in regulatory clinical trials.[1]At doses of 25 to 50mg and in terms of treatment–placebodifference, it reduces LPS by 6 to 12minutes, reduces WASO by 10 to 23minutes, and increases subjective TST by 10 to 22minutes.[1][18]Daridorexant has also been found to improve daytime functioning at a dose of 50mg but not at 25mg.[17]

Network meta-analyseshave assessed the sleep-promoting effects of orexin receptor antagonists and have compared them between one another as well as to other sleep aids includingbenzodiazepines,Z-drugs,antihistamines,sedativeantidepressants(e.g.,trazodone,doxepin,amitriptyline,mirtazapine), andmelatonin receptor agonists.[19][20][21][22]A majorsystematic reviewand network meta-analysis of insomnia medications published in 2022 found that daridorexant had aneffect size(standardized mean difference(SMD)) againstplacebofor treatment of insomnia at 4weeks of 0.23 (95%CITooltip confidence interval–0.01 to 0.48).[19]This was similar to but numerically lower than the effect sizes at 4weeks forsuvorexant(SMD 0.31, 95% CI 0.01 to 0.62) andlemborexant(SMD 0.36, 95% CI 0.08 to 0.63).[19]Benzodiazepines and Z-drugs generally showed larger effect sizes than orexin receptor antagonists (e.g., SMDs of 0.45 to 0.83).[19]The review concluded on the basis of daridorexant's small effect size that it did not show an overall material benefit in the treatment of insomnia.[19]Conversely, it concluded that lemborexant—as well as the Z-drugeszopiclone—had the best profiles overall in terms ofefficacy,tolerability,andacceptabilityamong all of the assessed insomnia medications.[19]

Orexin receptor antagonists are not used asfirst-line treatmentsfor insomnia due to their costs and concerns about possiblemisuse liability.[20]

Populationpharmacokineticmodeling indicates that differences between subjects do not require dose adjustments, and thatlean body weightandfat masseffect thepharmacokineticsof daridorexant better than other body size descriptors.[23]

Treatment with daridorexant is generally safe and well tolerated for up to one year, with improvements in sleep and daytime functioning persisting throughout treatment.[24]

TheDepartment of Defense (DOD)is testing the effectiveness of daridorexant in patients withpost-traumatic stress disorder (PTSD)as the link between insomnia and PTSD is well established.[25]

Available forms

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In the United States and Canada, daridorexant is available in the form of 25 and 50mgoraltablets.[1]It is provided as thesaltdaridorexant hydrochloride, with each tablet containing 27 or 54mg of this substance (equivalent to 25 or 50mg daridorexant).[1]

Contraindications

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Daridorexant iscontraindicatedin people withnarcolepsy.[1]It is not recommended in people with severehepatic impairment,whereas a lower maximum dose is recommended in people with moderate hepatic impairment.[1]Concomitant use of daridorexant with strongCYP3A4inhibitorsand moderate to strong CYP3A4inducersis not recommended and should be avoided due to unfavorable modification of daridorexant exposure.[1]

Side effects

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Side effectsof daridorexant includeheadache(6% at 25mg vs. 7% at 50mg vs. 5% forplacebo),somnolenceorfatigue(includes somnolence, sedation, fatigue, hypersomnia, and lethargy) (6% at 25mg vs. 5% at 50mg vs. 4% forplacebo),dizziness(2% at 25mg vs. 3% at 50mg vs. 2% for placebo), andnausea(0% at 25mg vs. 3% at 50mg vs. 2% for placebo).[1]No residual effects have been found after administration of 25mg daridorexant in the evening to either young or elderly individuals.[5]However, daridorexant may cause next-morning driving impairment at the start of treatment or in some individuals.[1]Orexin receptor antagonists like daridorexant may have less or no propensity for causingtolerancecompared to other sedatives and hypnotics based on animal studies.[8][1]Daridorexant did not produce signs ofwithdrawalordependenceupondiscontinuationin animal studies and clinical trials, and orexin receptor antagonists are not associated withrebound insomnia.[1][5]Loss of sleep-promoting effectiveness occurs rapidly upon discontinuation of daridorexant.[1]Preclinical researchhas suggested that orexin antagonists may reduceappetite,but daridorexant and other orexin antagonists have not been associated withweight lossinclinical trials.[16]Daridorexant may have a small risk ofsuicidal ideation.[26]

Orexin receptor antagonists can affect thereward systemand producedrug-likingresponses in humans.[27][16]Daridorexant at a dose of 50mg (the maximum recommended dose) showed significantly greater drug liking thanplacebobut significantly less drug liking thanzolpidem(30mg) andsuvorexant(150mg) in recreational sedative drug users.[1][28]At higher doses of 100 and 150mg (greater than the recommended maximum dose), drug liking with daridorexant was similar to that with zolpidem (30mg) and suvorexant (150mg).[1][28]In other studies, suvorexant showed similar drug liking compared to zolpidem but lower misuse potential on other measures (e.g., overall rate of misuse potential adverse events of 58% for zolpidem and 31% for suvorexant in recreational drug users).[29]No reports indicative ofmisuse liabilitywere observed in clinical trials with daridorexant, although these studies excluded participants with history of drug or alcohol misuse.[1][30][28]

Overdose

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There is limited clinical experience withoverdoseof daridorexant.[1]Overdose of the medication at a dose of up to four times the maximum recommended dose may result inadverse effectsincludingsomnolence,muscle weakness,cataplexy-like symptoms,sleep paralysis,attentiondisturbances,fatigue,headache,andconstipation.[1]There is no specificantidoteto overdose of daridorexant.[1]

Interactions

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CYP3A4inhibitorsandinducerscan increase and decrease exposure to daridorexant, respectively.[1][17][31]The weak CYP3A4 inhibitorranitidine(150mg) is predicted to increaseoverall exposureto daridorexant by 1.5-fold; the moderate CYP3A4 inhibitordiltiazem(240mg) increased exposure to daridorexant by 2.4-fold; and the strong CYP3A4 inhibitoritraconazole,on the basis ofphysiologically-based pharmacokinetic modeling,would be expected to increase daridorexant exposure by more than 4-fold.[1][17][31][7]Conversely, the moderate CYP3A4 inducerefavirenz(600mg) decreased daridorexant overall exposure by 35 to 60% and the strong CYP3A4 inducerrifampinsimilarly decreased daridorexant exposure by more than 50%.[1][31][7]Concomitant use of daridorexant with strong CYP3A4 inhibitors or with moderate or strong CYP3A4 inducers should be avoided, while it is recommended that the maximum dose of daridorexant be reduced with moderate CYP3A4 inhibitors.[1][7]

Examples of important CYP3A4 modulators which are expected to interact with daridorexant include the strong CYP3A4 inhibitorsboceprevir,clarithromycin,conivaptan,indinavir,itraconazole,ketoconazole,lopinavir,nefazodone,nelfinavir,posaconazole,ritonavir,saquinavir,telaprevir,andtelithromycin(concomitant use not recommended); the moderate CYP3A4 inhibitorsamprenavir,aprepitant,atazanavir,ciprofloxacin,diltiazem,dronedarone,erythromycin,fluconazole,fluvoxamine,fosamprenavir,grapefruit juice,imatinib,andverapamil(lower doses of daridorexant recommended); and the strong CYP3A4 inducersapalutamide,carbamazepine,efavirenz,enzalutamide,phenytoin,rifampin,andSt. John's wort(expected to decrease daridorexant effectiveness).[1][32][5]

GastricpHmodifiers likefamotidinecan decreasepeak levelsof daridorexant without affecting total exposure.[1]Alcoholandselective serotonin reuptake inhibitors(SSRIs) likecitalopramhave not shown significantpharmacokineticinteractionswith daridorexant.[1]Coadministration of daridorexant with othersedativeslikebenzodiazepines,opioids,tricyclic antidepressants,and alcohol may increase the risk ofcentral nervous system depressionanddaytime impairment.[1][7]

Daridorexant has not been found to significantly influence the pharmacokinetics of other drugs includingmidazolam(a CYP3A4substrate),rosuvastatin(aBCRPsubstrate), and the SSRI citalopram (primarily aCYP2C19substrate).[1][7]

Pharmacology

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Pharmacodynamics

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Daridorexant acts as aselectivedualantagonistof theorexin (hypocretin) receptorsOX1andOX2.[5]Theaffinities(Ki) of daridorexant for the orexin receptors are 0.47nM for the OX1receptor and 0.93nM for the OX2receptor.[1]Its Kbvalues for the human orexin receptors have been reported to be 0.5nM for the OX1receptor and 0.8nM for the OX2receptor.[8]Hence, daridorexant is approximatelyequipotentin its antagonism of the orexin receptors.[8]Daridorexant isselectivefor the orexin receptors over many othertargets.[8]In contrast to certain other sedatives and hypnotics, daridorexant is not abenzodiazepineorZ-drugand does not interact withGABA receptors.[8]

Mechanism of action

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Theendogenousorexinneuropeptides,orexin Aandorexin B,are involved in the regulation ofsleep–wake cyclesand act to promotewakefulness.[33][16][7]Deficiency of orexin signaling is thought to be the primary cause of thesleep disordernarcolepsy.[33][16]Disturbances in orexin signaling may also be involved ininsomnia.[33]Research suggests that orexin signaling may change with age, and this has been implicated inage-relatedsleep disturbances.[33]By blocking the actions of orexins and modulating sleep–wake cycles, orexin receptor antagonists like daridorexant reduce wakefulness and improve sleep.[33][16][7]The sleep-promoting effects of dual orexin receptor antagonists are thought to be mediated specifically by blockade of the OX2receptor in thelateral hypothalamus.[16]Although narcoleptic symptoms were a theoretical concern during the development of orexin receptor antagonists, this has not been observed in clinical trials of these agents.[33]

Pharmacokinetics

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Daridorexant levels after a single oral dose of 50 to 150mg daridorexant in healthy recreational sedative drug users.[28]

Absorption

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Theabsolute bioavailabilityof daridorexant is 62%.[1][7]The pooraqueous solubilityof daridorexant limits itsbioavailability.[7]It reachespeak concentrationswithin 1 to 2hours following a dose.[1][7]Food prolonged thetime to peakby 1.3 to 2hours and decreased the peak concentrations by 16 to 24%, but did not affectarea-under-the-curve concentrations.[1][7]

Distribution

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Thevolume of distributionof daridorexant is 31L.[1][7]Itsplasma protein bindingis 99.7%.[1][7]Theplasma-to-blood ratioof daridorexant is 0.64.[1]Daridorexant is alipophilicmolecule and effectively crosses theblood–brain barrierin animals.[8][7]

Metabolism

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Daridorexant is extensivelymetabolizedprimarily byCYP3A4(89%).[1][7]Othercytochrome P450enzymescontribute individually to less than 3% of theclearanceof daridorexant.[1]Daridorexant has 77 identifiedmetabolites.[7]Its major metabolites are less active than daridorexant as orexin receptor antagonists.[7]

Recently, a study was carried out using human livermicrosomesreported that daridorexant underwent 3 reaction;hydroxylationat the methyl group of the benzimidazole moiety, oxidative O-demethylationof the anisole to the correspondingphenol,andhydroxylationto a 4-hydroxy piperidinol derivative. Researchers proved that the chemical structures of the benzylic alcohol and thephenolare products of standardCYP450reactions; while the latter hydroxylation product was incompatible with the initially postulated hydroxylation of thepyrrolidinering, hence they suggested that humanmonooxygenaseCYP3A4catalyzes theintramolecularrearrangementof daridorexant. In detail, they proposed the following mechanism,hydroxylationin 5-position of thepyrrolidinering initially will yield a cyclichemiaminalwhich subsequently willhydrolyzeto a ring-openaminoaldehyde.Afterwards,cyclizationof the latter onto one of the nitrogen atoms of thebenzimidazolemoiety will yield the final 4-hydroxy piperidinolmetabolite.[34]

Elimination

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Daridorexant iseliminatedprimarily byfeces(57%) then byurine(28%).[1][7]It isexcretedmainly in the form ofmetabolites,with only trace amounts of the parent compound identified.[1][7]

The medication has anelimination half-lifeof about 8hours[1]or of 6 to 10hours.[5][7]The half-life of daridorexant may be longer in elderly individuals compared to young adults (9–10hours in the elderly versus 6hours in young adults).[7]Its half-life is shorter than that of otherorexin receptor antagonistssuch assuvorexant(12hours) andlemborexant(~18–55hours).[5]The relatively short half-life of daridorexant may allow for reduced daytime sedation.[5][16]Theduration of actionof daridorexant in terms of sedative effects is approximately 8hours with a 50mg dose.[5]

Chemistry

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Daridorexant is asmall-moleculecompound.[8]Thechemical nameof daridorexant is (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.[35][1]Itsmolecular formulais C23H23N6O2Cl and itsmolecular weightis 450.93g/mol (or 487.38g/mol for the hydrochloride).[35][1]Daridorexant hydrochloride is a white to light yellowish powder.[1]Daridorexant is alipophiliccompound and daridorexant hydrochloride is very slightlysolublein water.[7][1]

History

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Daridorexant was originated byActelion Pharmaceuticalsand was further developed byIdorsia.[4][9][36]It waspatentedin 2013[37]and was first described in thescientific literaturein 2017.[38][39][40]It was in development for 25 years by the husband-wife team Jean-Paul andMartine Clozel.[41]Daridorexant was approved for medical use in the United States in January 2022[1][11]and became available in May 2022.[12]

On 24 February 2022, theCommittee for Medicinal Products for Human Use(CHMP) of theEuropean Medicines Agency(EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Quviviq, intended for the treatment of insomnia.[4][36]On 29 April 2022, daridorexant was authorized for use in theEuropean Union.[13]It was the first orexin receptor antagonist to become available for use in the European Union.[13][42](The earlier orexin receptor antagonistssuvorexantandlemborexantare not available in the European Union.)[43][44][45][46]Regulatory review is also ongoing inCanadaandSwitzerlandand is planned for theUnited Kingdom.[17][9][needs update]

Society and culture

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Daridorexant is aschedule IVcontrolled substanceunder theControlled Substances Actin the United States.[1][14][15]

Daridorexant (Quviviq) was approved for medical use in the European Union in April 2022.[4][47]

Daridorexant (Quviviq) was approved by Health Canada in April 2023.[48]

References

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