 | |
 Above: structure of daridorexantBelow: 3D representation of a daridorexant molecule | |
| Clinical data | |
|---|---|
| Trade names | Quviviq |
| Other names | Nemorexant; ACT-541468, Daridorexant hydrochloride (USANUS) |
| License data | |
| Routes of administration | By mouth[1] |
| Drug class | Dual orexin receptor antagonist;Hypnotic;Sedative |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 62%[1] |
| Protein binding | 99.7%[1] |
| Metabolism | Extensive (mainlyCYP3A4 (89%))[1] |
| Onset of action | Tmax: 1–2 hours (delayed by 1.3 hours with food)[1] |
| Eliminationhalf-life | 8 hours (6–10 hours)[1][5] |
| Duration of action | ~8 hours (50 mg)[5] |
| Excretion | Feces: ~57%[1] Urine: ~28%[1] |
| Identifiers | |
| |
| CAS Number |
|
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII |
|
| KEGG | |
| ChEMBL |
|
| PDB ligand | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.353.123 |
| Chemical and physical data | |
| Formula | C23H23ClN6O2 |
| Molar mass | 450.93 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Daridorexant, sold under the brand nameQuviviq, is anorexin antagonistmedication which is used for the treatment ofinsomnia.[1][4][6][7][8] Daridorexant is takenby mouth.[1][4][7]
Side effects of daridorexant includeheadache,somnolence, andfatigue.[1][7] The medication is adual orexin receptor antagonist (DORA).[9][7][10][8] It acts as aselective dualantagonist of theorexin receptorsOX1 andOX2.[9][10][8] Compared to other marketed OX antagonists, daridorexant has a relatively shortelimination half-life of 8 hours and atime to peak of about 1 to 2 hours.[1][7][5] It is not abenzodiazepine orZ-drug and 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 substance in the United States and may have a modestpotential for misuse.[1][14][15] Besides daridorexant, other orexin receptor antagonists, likesuvorexant andlemborexant, have also been introduced.[16][17]
Daridorexant isindicated for the treatment of adults withinsomnia characterized by difficulties withsleep onset and/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 50 mg and in terms of treatment–placebo difference, it reduces LPS by 6 to 12 minutes, reduces WASO by 10 to 23 minutes, and increases subjective TST by 10 to 22 minutes.[1][18] Daridorexant has also been found to improve daytime functioning at a dose of 50 mg but not at 25 mg.[17]
Network meta-analyses have 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 review and network meta-analysis of insomnia medications published in 2022 found that daridorexant had aneffect size (standardized mean difference (SMD)) againstplacebo for treatment of insomnia at 4 weeks 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 4 weeks 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, andacceptability among all of the assessed insomnia medications.[19]
Orexin receptor antagonists are not used asfirst-line treatments for insomnia due to their costs and concerns about possiblemisuse liability.[20]
Populationpharmacokinetic modeling indicates that differences between subjects do not require dose adjustments, and thatlean body weight andfat mass effect thepharmacokinetics of 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]
In the United States and Canada, daridorexant is available in the form of 25 and 50 mgoraltablets.[1] It is provided as thesalt daridorexant hydrochloride, with each tablet containing 27 or 54 mg of this substance (equivalent to 25 or 50 mg daridorexant).[1]
Daridorexant iscontraindicated in 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 strongCYP3A4inhibitors and moderate to strong CYP3A4inducers is not recommended and should be avoided due to unfavorable modification of daridorexant exposure.[1]
Side effects of daridorexant includeheadache (6% at 25 mg vs. 7% at 50 mg vs. 5% forplacebo),somnolence orfatigue (includes somnolence, sedation, fatigue, hypersomnia, and lethargy) (6% at 25 mg vs. 5% at 50 mg vs. 4% forplacebo),dizziness (2% at 25 mg vs. 3% at 50 mg vs. 2% for placebo), andnausea (0% at 25 mg vs. 3% at 50 mg vs. 2% for placebo).[1] No residual effects have been found after administration of 25 mg 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 causingtolerance compared to other sedatives and hypnotics based on animal studies.[8][1] Daridorexant did not produce signs ofwithdrawal ordependence upondiscontinuation in 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 research has suggested that orexin antagonists may reduceappetite, but daridorexant and other orexin antagonists have not been associated withweight loss inclinical trials.[16] Daridorexant may have a small risk ofsuicidal ideation.[26]
Orexin receptor antagonists can affect thereward system and producedrug-liking responses in humans.[27][16] Daridorexant at a dose of 50 mg (the maximum recommended dose) showed significantly greater drug liking thanplacebo but significantly less drug liking thanzolpidem (30 mg) andsuvorexant (150 mg) in recreational sedative drug users.[1][28] At higher doses of 100 and 150 mg (greater than the recommended maximum dose), drug liking with daridorexant was similar to that with zolpidem (30 mg) and suvorexant (150 mg).[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 liability were observed in clinical trials with daridorexant, although these studies excluded participants with history of drug or alcohol misuse.[1][30][28]
There is limited clinical experience withoverdose of daridorexant.[1] Overdose of the medication at a dose of up to four times the maximum recommended dose may result inadverse effects includingsomnolence,muscle weakness,cataplexy-like symptoms,sleep paralysis,attention disturbances,fatigue,headache, andconstipation.[1] There is no specificantidote to overdose of daridorexant.[1]
CYP3A4inhibitors andinducers can increase and decrease exposure to daridorexant, respectively.[1][17][31] The weak CYP3A4 inhibitorranitidine (150 mg) is predicted to increaseoverall exposure to daridorexant by 1.5-fold; the moderate CYP3A4 inhibitordiltiazem (240 mg) 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 (600 mg) decreased daridorexant overall exposure by 35 to 60% and the strong CYP3A4 inducerrifampin similarly 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]
GastricpH modifiers likefamotidine can decreasepeak levels of daridorexant without affecting total exposure.[1]Alcohol andselective serotonin reuptake inhibitors (SSRIs) likecitalopram have not shown significantpharmacokineticinteractions with daridorexant.[1] Coadministration of daridorexant with othersedatives likebenzodiazepines,opioids,tricyclic antidepressants, and alcohol may increase the risk ofcentral nervous system depression anddaytime impairment.[1][7]
Daridorexant has not been found to significantly influence the pharmacokinetics of other drugs includingmidazolam (a CYP3A4substrate),rosuvastatin (aBCRP substrate), and the SSRI citalopram (primarily aCYP2C19 substrate).[1][7]
Daridorexant acts as aselective dualantagonist of theorexin (hypocretin) receptorsOX1 andOX2.[5] Theaffinities (Ki) of daridorexant for the orexin receptors are 0.47 nM for the OX1 receptor and 0.93 nM for the OX2 receptor.[1] Its Kb values for the human orexin receptors have been reported to be 0.5 nM for the OX1 receptor and 0.8 nM for the OX2 receptor.[8] Hence, daridorexant is approximatelyequipotent in its antagonism of the orexin receptors.[8] Daridorexant isselective for the orexin receptors over many othertargets.[8] In contrast to certain other sedatives and hypnotics, daridorexant is not abenzodiazepine orZ-drug and does not interact withGABA receptors.[8]
Theendogenousorexinneuropeptides,orexin A andorexin B, are involved in the regulation ofsleep–wake cycles and 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 OX2 receptor 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]
Theabsolute bioavailability of daridorexant is 62%.[1][7] The pooraqueous solubility of daridorexant limits itsbioavailability.[7] It reachespeak concentrations within 1 to 2 hours following a dose.[1][7] Food prolonged thetime to peak by 1.3 to 2 hours and decreased the peak concentrations by 16 to 24%, but did not affectarea-under-the-curve concentrations.[1][7]
Thevolume of distribution of daridorexant is 31 L.[1][7] Itsplasma protein binding is 99.7%.[1][7] Theplasma-to-blood ratio of daridorexant is 0.64.[1] Daridorexant is alipophilic molecule and effectively crosses theblood–brain barrier in animals.[8][7]
Daridorexant is extensivelymetabolized primarily byCYP3A4 (89%).[1][7] Othercytochrome P450enzymes contribute individually to less than 3% of theclearance of 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 livermicrosomes reported that daridorexant underwent 3 reaction;hydroxylation at the methyl group of the benzimidazole moiety, oxidative O-demethylation of the anisole to the correspondingphenol, andhydroxylation to a 4-hydroxy piperidinol derivative. Researchers proved that the chemical structures of the benzylic alcohol and thephenol are products of standardCYP450 reactions; while the latter hydroxylation product was incompatible with the initially postulated hydroxylation of thepyrrolidine ring, hence they suggested that humanmonooxygenaseCYP3A4 catalyzes theintramolecularrearrangement of daridorexant. In detail, they proposed the following mechanism,hydroxylation in 5-position of thepyrrolidine ring initially will yield a cyclichemiaminal which subsequently willhydrolyze to a ring-openaminoaldehyde. Afterwards,cyclization of the latter onto one of the nitrogen atoms of thebenzimidazole moiety will yield the final 4-hydroxy piperidinolmetabolite.[34]
Daridorexant iseliminated primarily byfeces (57%) then byurine (28%).[1][7] It isexcreted mainly in the form ofmetabolites, with only trace amounts of the parent compound identified.[1][7]
The medication has anelimination half-life of about 8 hours[1] or of 6 to 10 hours.[5][7] The half-life of daridorexant may be longer in elderly individuals compared to young adults (9–10 hours in the elderly versus 6 hours in young adults).[7] Its half-life is shorter than that of otherorexin receptor antagonists such assuvorexant (12 hours) andlemborexant (~18–55 hours).[5] The relatively short half-life of daridorexant may allow for reduced daytime sedation.[5][16] Theduration of action of daridorexant in terms of sedative effects is approximately 8 hours with a 50 mg dose.[5]
Daridorexant is asmall-molecule compound.[8] Thechemical name of 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 formula is C23H23N6O2Cl and itsmolecular weight is 450.93 g/mol (or 487.38 g/mol for the hydrochloride).[35][1] Daridorexant hydrochloride is a white to light yellowish powder.[1] Daridorexant is alipophilic compound and daridorexant hydrochloride is very slightlysoluble in water.[7][1]
Daridorexant was originated byActelion Pharmaceuticals and was further developed byIdorsia.[4][9][36] It waspatented in 2013[37] and was first described in thescientific literature in 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 antagonistssuvorexant andlemborexant are not available in the European Union.)[43][44][45][46] Regulatory review is also ongoing inCanada andSwitzerland and is planned for theUnited Kingdom.[17][9][needs update]
Daridorexant is aschedule IVcontrolled substance under theControlled Substances Act in 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]
This article incorporates text from this source, which is in thepublic domain.