Daridorexant

From Wikipedia, the free encyclopedia

Daridorexant
Nemorexant.svg
Clinical data
Trade namesQuviviq
Other namesNemorexant; ACT-541468
License data
Routes of
administration		By mouth[1]
Drug classOrexin antagonist
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Bioavailability62%[1]
Protein binding99.7%[1]
MetabolismExtensive (mainly CYP3A4 (89%))[1]
Onset of actionTmax: 1–2 hours (delayed by 1.3 hours with food)[1]
Elimination half-life8 hours (6–10 hours)[1][2]
Duration of action~8 hours (50 mg)[2][2]
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
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
FormulaC23H23ClN6O2
Molar mass450.93 g·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

Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication that is used for the treatment of insomnia.[1][3] It is taken by mouth.[1]

Side effects of daridorexant include headache and somnolence or fatigue.[1] The medication is a dual orexin receptor antagonist (DORA).[4][5][3] It acts as a selective dual antagonist of the orexin receptors OX1 and OX2.[4][5][3] The medication has a relatively short elimination half-life of about 8 hours.[1][2] Daridorexant is not a benzodiazepine or Z-drug and does not interact with GABA receptors, instead having a distinct mechanism of action.[3]

Daridorexant was approved for medical use in the United States in January 2022.[1][6][7] It is expected to become available in May 2022.[8] The medication was originated by Actelion Pharmaceuticals and was developed by Idorsia Pharmaceuticals.[4] It is a controlled substance in the United States.[1][7]

Medical uses[]

Daridorexant is indicated for the treatment of adults with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.[1]

Available forms[]

Daridorexant is available in the form of 25 and 50 mg oral tablets.[1] It is provided as the salt daridorexant hydrochloride, with each tablet containing 27 or 54 mg of this substance (equivalent to 25 or 50 mg daridorexant).[1]

Contraindications[]

Daridorexant is contraindicated in people with narcolepsy.[1]

Side effects[]

Side effects of daridorexant include somnolence or fatigue (combined preferred terms of "somnolence", "lethargy", "fatigue", "sluggishness"; 6.9–9.6% vs. 1.3% for placebo), headache (4.5–5.9% vs. 3.4% for placebo), and nightmares or abnormal dreams (0.9–2.2% vs. 0.9% for placebo).[1] No residual effects have been found after administration of 25 mg daridorexant in the evening to either young or elderly individuals.[2][2] 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 causing tolerance compared to other sedatives and hypnotics based on animal studies.[3][1] Daridorexant did not produce signs of withdrawal or dependence upon discontinuation in animal studies and clinical trials, and orexin receptor antagonists are not associated with rebound insomnia.[1][2] Preclinical research has suggested that orexin antagonists may reduce appetite, but daridorexant and other orexin antagonists have not been associated with weight loss in rigorous clinical trials.[9]

Orexin receptor antagonists can affect the reward system and produce drug-liking responses in humans.[10][1][11] Daridorexant at a dose of 50 mg (the maximum recommended dose) showed significantly greater drug liking than placebo but significantly less drug liking than zolpidem (30 mg) and suvorexant (150 mg) in recreational sedative drug users.[1][11] At 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][11] 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).[12] No reports indicative of misuse liability were observed in large clinical trials with daridorexant, although these studies excluded participants with history of drug or alcohol misuse.[1][13][11]

Overdose[]

There is limited clinical experience with overdose of daridorexant.[1] Overdose of the medication at a dose of up to four times the maximum recommended dose may result in adverse effects including somnolence, muscle weakness, catalepsy-like symptoms, sleep paralysis, attention disturbances, fatigue, headache, and constipation.[1] There is no specific antidote to overdose of daridorexant.[1]

Interactions[]

CYP3A4 inhibitors like ranitidine and diltiazem and CYP3A4 inducers like efavirenz can increase and decrease exposure to daridorexant, respectively.[1] Concomitant use of daridorexant with strong CYP3A4 inhibitors or moderate or strong CYP3A4 inducers should be avoided, while it is recommended that the maximum dose of daridorexant be limited with moderate CYP3A4 inhibitors.[1] Gastric pH modifiers like famotidine can decrease peak levels of daridorexant without affecting total exposure.[1] Alcohol and selective serotonin reuptake inhibitors (SSRIs) like citalopram have not shown significant pharmacokinetic interactions with daridorexant.[1] Coadministration of daridorexant with other sedatives like benzodiazepines, opioids, tricyclic antidepressants, and alcohol may increase the risk of central nervous system depression and daytime impairment.[1] Daridorexant has not been found to significantly influence the pharmacokinetics of other drugs including midazolam (CYP3A4 substrate), rosuvastatin (BCRP substrate), and the SSRI citalopram.[1]

Pharmacology[]

Pharmacodynamics[]

Daridorexant acts as a selective dual antagonist of the orexin (hypocretin) receptors OX1 and OX2.[2] The affinities (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.[3] Hence, daridorexant is approximately equipotent in its antagonism of the orexin receptors.[3] Daridorexant is selective for the orexin receptors over many other targets.[3] In contrast to certain other sedatives and hypnotics, daridorexant is not a benzodiazepine or Z-drug and does not interact with GABA receptors.[3]

Pharmacokinetics[]

Daridorexant levels after a single oral dose of 50 to 150 mg daridorexant in healthy recreational sedative drug users.[11]

Absorption[]

The absolute bioavailability of daridorexant is 62%.[1] It reaches peak concentrations within 1 to 2 hours following a dose.[1] Food prolonged the time to peak by 1.3 hours and decreased the peak concentrations by 16%, but did not affect area-under-the-curve concentrations.[1]

Distribution[]

The volume of distribution of daridorexant is 31 L.[1] Its plasma protein binding is 99.7%.[1] The plasma-to-blood ratio of daridorexant is 0.64.[1] Daridorexant effectively crosses the blood–brain barrier in animals.[3]

Metabolism[]

Daridorexant is extensively metabolized primarily by CYP3A4 (89%).[1] Other cytochrome P450 enzymes contribute individually to less than 3% of the clearance of daridorexant.[1]

Elimination[]

Daridorexant is eliminated primarily by feces (57%) then by urine (28%).[1] It is excreted mainly in the form of metabolites, with only trace amounts of the parent compound identified.[1]

The medication has an elimination half-life of about 8 hours[1] or of 6 to 10 hours.[2] Its half-life is shorter than that of other orexin receptor antagonists such as suvorexant (12 hours) and lemborexant (~18–55 hours).[2] The relatively short half-life of daridorexant may allow for reduced daytime sedation.[2][9] The duration of action of daridorexant in terms of sedative effects is approximately 8 hours with a 50 mg dose.[2][2]

Chemistry[]

The chemical name of daridorexant is s (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.[14][1] Its molecular formula is C23H23N6O2Cl and its molecular weight is 450.93 g/mol (or 487.38 g/mol for the hydrochloride).[14][1] Daridorexant hydrochloride is a white to light yellowish powder and is very slightly soluble in water.[1]

History[]

Daridorexant was approved for medical use in the United States in January 2022.[1] Although approved, daridorexant is not yet available in this country; it is expected to become available in May 2022.[8]

On 24 February 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Quviviq, intended for the treatment of insomnia.[15] The applicant for this medicinal product is Idorsia Pharmaceuticals Deutschland GmbH.[15]

Society and culture[]

Legal status[]

Daridorexant is classified as a controlled substance in the United States.[1][7] Its schedule category is still pending.[1]

References[]

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf[bare URL PDF]
  2. ^ a b c d e f g h i j k l m Muehlan C, Vaillant C, Zenklusen I, Kraehenbuehl S, Dingemanse J (November 2020). "Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders". Expert Opin Drug Metab Toxicol. 16 (11): 1063–1078. doi:10.1080/17425255.2020.1817380. PMID 32901578.
  3. ^ a b c d e f g h i j Roch C, Bergamini G, Steiner MA, Clozel M (October 2021). "Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia". Psychopharmacology (Berl). 238 (10): 2693–2708. doi:10.1007/s00213-021-05954-0. PMC 8455402. PMID 34415378.
  4. ^ a b c "Daridorexant - Idorsia Pharmaceuticals - AdisInsight".
  5. ^ a b Equihua-Benítez AC, Guzmán-Vásquez K, Drucker-Colín R (July 2017). "Understanding sleep-wake mechanisms and drug discovery". Expert Opin Drug Discov. 12 (7): 643–657. doi:10.1080/17460441.2017.1329818. PMID 28511597.
  6. ^ "Daridorexant: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 11 January 2022.
  7. ^ a b c "Idorsia receives US FDA approval of Quviviq (daridorexant)" (Press release). Idorsia Pharmaceuticals. 10 January 2022. Retrieved 11 January 2022 – via GlobeNewswire.
  8. ^ a b Aungst, Christina (10 February 2022). "FDA Approves Daridorexant (Quviviq) to Treat Insomnia". GoodRx. In January 2022, the FDA approved daridorexant (Quviviq) to treat insomnia in adults. It’s expected to be available in May 2022. [...] Daridorexant is expected to be available in May 2022. Because it’s a controlled substance, the U.S. Drug Enforcement Administration (DEA) reviews this medication after the FDA. The DEA is required to conduct this review within 120 days (4 months) of the FDA’s approval of a controlled substance.
  9. ^ a b Jacobson LH, Hoyer D, de Lecea L (January 2022). "Hypocretins (orexins): The ultimate translational neuropeptides". J Intern Med. doi:10.1111/joim.13406. PMID 35043499.
  10. ^ Calipari ES, España RA (2012). "Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms". Front Behav Neurosci. 6: 54. doi:10.3389/fnbeh.2012.00054. PMC 3423791. PMID 22933994.
  11. ^ a b c d e Ufer M, Kelsh D, Schoedel KA, Dingemanse J (September 2021). "Abuse potential assessment of the new dual orexin receptor antagonist daridorexant in recreational sedative drug users as compared to suvorexant and zolpidem". Sleep. doi:10.1093/sleep/zsab224. PMID 34480579.
  12. ^ Patel KV, Aspesi AV, Evoy KE (April 2015). "Suvorexant: a dual orexin receptor antagonist for the treatment of sleep onset and sleep maintenance insomnia". Ann Pharmacother. 49 (4): 477–83. doi:10.1177/1060028015570467. PMID 25667197.
  13. ^ Mignot E, Mayleben D, Fietze I, Leger D, Zammit G, Bassetti CL, Pain S, Kinter DS, Roth T (February 2022). "Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials". Lancet Neurol. 21 (2): 125–139. doi:10.1016/S1474-4422(21)00436-1. PMID 35065036.
  14. ^ a b https://pubchem.ncbi.nlm.nih.gov/compound/91801202
  15. ^ a b "Quviviq: Pending EC decision". European Medicines Agency. 24 February 2022. Retrieved 27 February 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

External links[]

  • "Daridorexant". Drug Information Portal. U.S. National Library of Medicine.
Retrieved from ""