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| pregnancy_category =
| pregnancy_category =
| legal_status = Uncontrolled
| legal_status = Uncontrolled
| routes_of_administration = [[Mouth|Oral]]
| routes_of_administration = [[Oral administration|Oral]]
<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
| bioavailability =
| bioavailability =
| metabolism = Liver ([[CYP2D6]])<ref name="urlwww.page-meeting.org">{{cite web | url = http://www.page-meeting.org/pdf_assets/2259-posterPAGE2008_SP.pdf | title = A population analysis on the effects of the CYP2D6 deficiency on pharmacokinetics and exposure of esmirtazapine in healthy volunteers}}</ref>
| metabolism = Liver ([[CYP2D6]])<ref name="urlwww.page-meeting.org">{{cite web | vauthors = Lillin-de Vries O, Kerbusch T, de Kam PJ, Ivgy-May N, Bursi R | url = http://www.page-meeting.org/pdf_assets/2259-posterPAGE2008_SP.pdf | title = A population analysis on the effects of the CYP2D6 deficiency on pharmacokinetics and exposure of esmirtazapine in healthy volunteers | publisher = Schering-Plough Corporation | location = Oss, The Netherlands }}</ref>
| elimination_half-life = 10 hours<ref name="insommnia">{{cite journal |last1=Ruwe |first1=Frank |last2=IJzerman-Boon |first2=Pieta |last3=Roth |first3=Thomas |last4=Zammit |first4=Gary |last5=Ivgy-May |first5=Neely |title=A Phase 2 Randomized Dose-Finding Study With Esmirtazapine in Patients With Primary Insomnia |journal=Journal of Clinical Psychopharmacology |date=October 2016 |volume=36 |issue=5 |pages=457–464 |doi=10.1097/JCP.0000000000000546|pmid=27482970 |s2cid=25639396 }}</ref>
| elimination_half-life = 10 hours<ref name="insommnia">{{cite journal | vauthors = Ruwe F, IJzerman-Boon P, Roth T, Zammit G, Ivgy-May N | title = A Phase 2 Randomized Dose-Finding Study With Esmirtazapine in Patients With Primary Insomnia | journal = Journal of Clinical Psychopharmacology | volume = 36 | issue = 5 | pages = 457–464 | date = October 2016 | pmid = 27482970 | doi = 10.1097/JCP.0000000000000546 | s2cid = 25639396 }}</ref>
| excretion =
| excretion =
<!--Identifiers-->
<!--Identifiers-->
Line 44: Line 44:
| melting_high = 116
| melting_high = 116
| solubility = Soluble in [[methanol]] and [[chloroform]]
| solubility = Soluble in [[methanol]] and [[chloroform]]
| sol_units = &nbsp;
}}
}}


'''Esmirtazapine''' ('''ORG-50,081''') is a [[tetracyclic antidepressant]] drug which was under development by [[Organon International|Organon]] for the treatment of [[insomnia]] and [[vasomotor]] [[symptom]]s (e.g., [[hot flash]]es) associated with [[menopause]].<ref name="urlFuture Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD -- Neurotransmitter.net">{{cite web | url = http://www.neurotransmitter.net/newdrugs.html | title = Future Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD -- Neurotransmitter.net }}</ref><ref name="urlA Long-Term Safety Study of Org 50081 in Elderly Outpatients With Chronic Primary Insomnia (176005)(P05697) - Full Text View - ClinicalTrials.gov">{{cite document | url = http://clinicaltrials.gov/ct2/show/NCT00561574 | title = A Long-Term Safety Study of Org 50081 in Elderly Outpatients With Chronic Primary Insomnia (176005)(P05697) - Full Text View - ClinicalTrials.gov | date = 7 January 2021 }}</ref><ref name="pmid18673166">{{cite journal |vauthors=Teegarden BR, Al Shamma H, Xiong Y | title = 5-HT(2A) inverse-agonists for the treatment of insomnia | journal = Current Topics in Medicinal Chemistry | volume = 8 | issue = 11 | pages = 969–76 | year = 2008 | pmid = 18673166 | doi = 10.2174/156802608784936700}}</ref><ref name="pmid19775194">{{cite journal | author = Lewis V | title = Undertreatment of menopausal symptoms and novel options for comprehensive management | journal = Current Medical Research and Opinion | volume = 25 | issue = 11 | pages = 2689–98 |date=November 2009 | pmid = 19775194 | doi = 10.1185/03007990903240519 | s2cid = 206964530 }}</ref> Esmirtazapine is the (''S'')-(+)-[[enantiomer]] of [[mirtazapine]] and possesses similar overall [[pharmacology]], including [[inverse agonist]] actions at [[H1 receptor|H<sub>1</sub>]] and [[5-HT2 receptor|5-HT<sub>2</sub> receptor]]s and [[receptor antagonist|antagonist]] actions at [[alpha-2 adrenergic receptor|α<sub>2</sub>-adrenergic receptor]]s.<ref name="urlFuture Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD -- Neurotransmitter.net"/><ref name="isbn0-521-88663-5">{{cite book | title = Depression and bipolar disorder: Stahl's essential psychopharmacology | publisher = Cambridge University Press | location = Cambridge, UK | year = 2008 | isbn = 978-0-521-88663-5 | url = https://books.google.com/books?id=zqvVZOea2JAC&q=esmirtazapine&pg=PA112}}</ref>
'''Esmirtazapine''' ('''ORG-50,081''') is a [[tetracyclic antidepressant]] drug that was under development by [[Organon International|Organon]] for the treatment of [[insomnia]] and [[vasomotor]] [[symptom]]s (e.g., [[hot flash]]es) associated with [[menopause]].<ref name="urlFuture Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD -- Neurotransmitter.net">{{cite web | url = http://www.neurotransmitter.net/newdrugs.html | title = Future Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD | work = Neurotransmitter.net }}</ref><ref name="NCT00561574">{{ClinicalTrialsGov|NCT00561574|A Long-Term Safety Study of Org 50081 in Elderly Outpatients With Chronic Primary Insomnia (176005)}}</ref><ref name="pmid18673166">{{cite journal | vauthors = Teegarden BR, Al Shamma H, Xiong Y | title = 5-HT(2A) inverse-agonists for the treatment of insomnia | journal = Current Topics in Medicinal Chemistry | volume = 8 | issue = 11 | pages = 969–976 | year = 2008 | pmid = 18673166 | doi = 10.2174/156802608784936700 }}</ref><ref name="pmid19775194">{{cite journal | vauthors = Lewis V | title = Undertreatment of menopausal symptoms and novel options for comprehensive management | journal = Current Medical Research and Opinion | volume = 25 | issue = 11 | pages = 2689–2698 | date = November 2009 | pmid = 19775194 | doi = 10.1185/03007990903240519 | s2cid = 206964530 }}</ref> Esmirtazapine is the (''S'')-(+)-[[enantiomer]] of [[mirtazapine]] and possesses similar overall [[pharmacology]], including [[inverse agonist]] actions at [[H1 receptor|H<sub>1</sub>]] and [[5-HT2 receptor|5-HT<sub>2</sub> receptor]]s and [[receptor antagonist|antagonist]] actions at [[alpha-2 adrenergic receptor|α<sub>2</sub>-adrenergic receptor]]s.<ref name="urlFuture Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD -- Neurotransmitter.net"/><ref name="isbn0-521-88663-5">{{cite book | vauthors = Stahl SM | chapter = Antidepresents | title = Depression and bipolar disorder: Stahl's essential psychopharmacology | edition = 3rd | publisher = Cambridge University Press | location = Cambridge, UK | year = 2008 | isbn = 978-0-521-88663-5 | chapter-url = https://books.google.com/books?id=zqvVZOea2JAC&q=esmirtazapine&pg=PA112}}</ref>


Notably, esmirtazapine has a shorter half life of around 10 hours, compared to R-mirtazapine and racemic mixture, which has a half-life of 18-40 hours.<ref name="insommnia"/> Merck has run several studies on low dose (3 - 4.5 mg) esmirtazapine for the treatment of insomnia. It is attractive for treating insomnia since it is a potent H1-inhibitor and a 5-HT2A antagonist.<ref>{{cite journal |last1=Ivgy-May |first1=Neely |last2=Ruwe |first2=Frank |last3=Krystal |first3=Andrew |last4=Roth |first4=Thomas |title=Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a randomized, 6-week sleep laboratory trial |journal=Sleep Medicine |date=1 July 2015 |volume=16 |issue=7 |pages=838–844 |doi=10.1016/j.sleep.2015.04.001|pmid=26047892 }}</ref><ref name="insommnia"/> Unlike low-dose mirtazapine, the half life (10 hours) is short enough that next-day sedation may be manageable, however, for people with CYP2D6 polymorphisms, which constitute a sizable fraction of the population, the half-life is expected to be quite a bit longer. Merck researchers claimed that the incidence of next-day sedation was not a problem in one of their studies, but this claim has been challenged (15% of patients complained of daytime sleepiness vs 3.5% in the placebo group).<ref>{{cite journal |last1=Ivgy-May |first1=Neely |last2=Hajak |first2=Goeran |last3=van Osta |first3=Gonnie |last4=Braat |first4=Sabine |last5=Chang |first5=Qing |last6=Roth |first6=Thomas |title=Efficacy and safety of esmirtazapine in adult outpatients with chronic primary insomnia: a randomized, double-blind placebo-controlled study and open-label extension |journal=Journal of Clinical Sleep Medicine |date=15 September 2020 |volume=16 |issue=9 |pages=1455–1467 |doi=10.5664/jcsm.8526|pmid=32351205 |pmc=7970588 }}</ref>
Notably, esmirtazapine has a shorter half life of around 10&nbsp;hours, compared to R-mirtazapine and racemic mixture, which has a half-life of 18–40&nbsp;hours.<ref name="insommnia"/> Merck has run several studies on low dose (3–4.5&nbsp;mg) esmirtazapine for the treatment of insomnia. It is attractive for treating insomnia since it is a potent H<sub>1</sub>-inhibitor and a 5-HT<sub>2A</sub> antagonist.<ref>{{cite journal | vauthors = Ivgy-May N, Ruwe F, Krystal A, Roth T | title = Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a randomized, 6-week sleep laboratory trial | journal = Sleep Medicine | volume = 16 | issue = 7 | pages = 838–844 | date = July 2015 | pmid = 26047892 | doi = 10.1016/j.sleep.2015.04.001 }}</ref><ref name="insommnia"/> Unlike low-dose mirtazapine, the half life (10&nbsp;hours) is short enough that next-day sedation may be manageable, however, for people with CYP2D6 polymorphisms, which constitute a sizable fraction of the population, the half-life is expected to be quite a bit longer. Merck researchers claimed that the incidence of next-day sedation was not a problem in one of their studies, but this claim has been challenged (15% of patients complained of daytime sleepiness vs 3.5% in the placebo group).<ref>{{cite journal | vauthors = Ivgy-May N, Hajak G, van Osta G, Braat S, Chang Q, Roth T | title = Efficacy and safety of esmirtazapine in adult outpatients with chronic primary insomnia: a randomized, double-blind placebo-controlled study and open-label extension | journal = Journal of Clinical Sleep Medicine | volume = 16 | issue = 9 | pages = 1455–1467 | date = September 2020 | pmid = 32351205 | pmc = 7970588 | doi = 10.5664/jcsm.8526 }}</ref>


In March 2010, Merck terminated its internal clinical development program for esmirtazapine for hot flashes and insomnia, "for strategic reasons".<ref>{{Cite web |url=http://www.merck.com/investors/financials/form-10-K-2009-final.pdf |title=Archived copy |access-date=2011-05-03 |archive-date=2011-08-05 |archive-url=https://web.archive.org/web/20110805215529/http://www.merck.com/investors/financials/form-10-K-2009-final.pdf |url-status=dead }}</ref>
In March 2010, Merck terminated its internal clinical development program for esmirtazapine for hot flashes and insomnia, "for strategic reasons".<ref>{{Cite web |url=http://www.merck.com/investors/financials/form-10-K-2009-final.pdf |title=Form 10-K | publisher = Merck & Co., Inc. |access-date=2011-05-03 |archive-date=2011-08-05 |archive-url=https://web.archive.org/web/20110805215529/http://www.merck.com/investors/financials/form-10-K-2009-final.pdf |url-status=dead }}</ref>


==See also==
== See also ==
* [[Cidoxepin]]
* [[Cidoxepin]]


==References==
== References ==
{{Reflist|2}}
{{Reflist|2}}


==External links==
== External links ==
*{{Commons category-inline}}
*{{Commons category-inline}}


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{{Serotonin receptor modulators}}
{{Serotonin receptor modulators}}
}}
}}
{{Tetracyclics}}


[[Category:Alpha-2 blockers]]
[[Category:Alpha-2 blockers]]
[[Category:Enantiopure drugs]]
[[Category:Enantiopure drugs]]
[[Category:H1 receptor antagonists]]
[[Category:H1 receptor antagonists]]
[[Category:Schering-Plough brands]]
[[Category:Drugs developed by Schering-Plough]]
[[Category:Merck & Co. brands]]
[[Category:Drugs developed by Merck & Co.]]
[[Category:Noradrenergic and specific serotonergic antidepressants]]
[[Category:Noradrenergic and specific serotonergic antidepressants]]
[[Category:Serotonin receptor antagonists]]
[[Category:Serotonin receptor antagonists]]
[[Category:Tetracyclic antidepressants]]
[[Category:Tetracyclic antidepressants]]
[[Category:Abandoned drugs]]


{{nervous-system-drug-stub}}
{{Organic-compound-stub}}

Latest revision as of 14:56, 29 February 2024

Esmirtazapine
Clinical data
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • In general: uncontrolled
Pharmacokinetic data
MetabolismLiver (CYP2D6)[2]
Elimination half-life10 hours[1]
Identifiers
  • (S)-1,2,3,4,10,14b-hexahydro-2-methylpyrazino(2,1-a)pyrido(2,3-c)(2)benzazepine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.056.994 Edit this at Wikidata
Chemical and physical data
FormulaC17H19N3
Molar mass265.360 g·mol−1
3D model (JSmol)
Melting point114 to 116 °C (237 to 241 °F)
Solubility in waterSoluble in methanol and chloroform 
  • CN1CCN2c3c(cccn3)Cc4ccccc4[C@H]2C1
  • InChI=1S/C17H19N3/c1-19-9-10-20-16(12-19)15-7-3-2-5-13(15)11-14-6-4-8-18-17(14)20/h2-8,16H,9-12H2,1H3/t16-/m1/s1 checkY
  • Key:RONZAEMNMFQXRA-MRXNPFEDSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Esmirtazapine (ORG-50,081) is a tetracyclic antidepressant drug that was under development by Organon for the treatment of insomnia and vasomotor symptoms (e.g., hot flashes) associated with menopause.[3][4][5][6] Esmirtazapine is the (S)-(+)-enantiomer of mirtazapine and possesses similar overall pharmacology, including inverse agonist actions at H1 and 5-HT2 receptors and antagonist actions at α2-adrenergic receptors.[3][7]

Notably, esmirtazapine has a shorter half life of around 10 hours, compared to R-mirtazapine and racemic mixture, which has a half-life of 18–40 hours.[1] Merck has run several studies on low dose (3–4.5 mg) esmirtazapine for the treatment of insomnia. It is attractive for treating insomnia since it is a potent H1-inhibitor and a 5-HT2A antagonist.[8][1] Unlike low-dose mirtazapine, the half life (10 hours) is short enough that next-day sedation may be manageable, however, for people with CYP2D6 polymorphisms, which constitute a sizable fraction of the population, the half-life is expected to be quite a bit longer. Merck researchers claimed that the incidence of next-day sedation was not a problem in one of their studies, but this claim has been challenged (15% of patients complained of daytime sleepiness vs 3.5% in the placebo group).[9]

In March 2010, Merck terminated its internal clinical development program for esmirtazapine for hot flashes and insomnia, "for strategic reasons".[10]

See also

[edit]

References

[edit]
  1. ^ a b c Ruwe F, IJzerman-Boon P, Roth T, Zammit G, Ivgy-May N (October 2016). "A Phase 2 Randomized Dose-Finding Study With Esmirtazapine in Patients With Primary Insomnia". Journal of Clinical Psychopharmacology. 36 (5): 457–464. doi:10.1097/JCP.0000000000000546. PMID 27482970. S2CID 25639396.
  2. ^ Lillin-de Vries O, Kerbusch T, de Kam PJ, Ivgy-May N, Bursi R. "A population analysis on the effects of the CYP2D6 deficiency on pharmacokinetics and exposure of esmirtazapine in healthy volunteers" (PDF). Oss, The Netherlands: Schering-Plough Corporation.
  3. ^ a b "Future Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD". Neurotransmitter.net.
  4. ^ Clinical trial number NCT00561574 for "A Long-Term Safety Study of Org 50081 in Elderly Outpatients With Chronic Primary Insomnia (176005)" at ClinicalTrials.gov
  5. ^ Teegarden BR, Al Shamma H, Xiong Y (2008). "5-HT(2A) inverse-agonists for the treatment of insomnia". Current Topics in Medicinal Chemistry. 8 (11): 969–976. doi:10.2174/156802608784936700. PMID 18673166.
  6. ^ Lewis V (November 2009). "Undertreatment of menopausal symptoms and novel options for comprehensive management". Current Medical Research and Opinion. 25 (11): 2689–2698. doi:10.1185/03007990903240519. PMID 19775194. S2CID 206964530.
  7. ^ Stahl SM (2008). "Antidepresents". Depression and bipolar disorder: Stahl's essential psychopharmacology (3rd ed.). Cambridge, UK: Cambridge University Press. ISBN 978-0-521-88663-5.
  8. ^ Ivgy-May N, Ruwe F, Krystal A, Roth T (July 2015). "Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a randomized, 6-week sleep laboratory trial". Sleep Medicine. 16 (7): 838–844. doi:10.1016/j.sleep.2015.04.001. PMID 26047892.
  9. ^ Ivgy-May N, Hajak G, van Osta G, Braat S, Chang Q, Roth T (September 2020). "Efficacy and safety of esmirtazapine in adult outpatients with chronic primary insomnia: a randomized, double-blind placebo-controlled study and open-label extension". Journal of Clinical Sleep Medicine. 16 (9): 1455–1467. doi:10.5664/jcsm.8526. PMC 7970588. PMID 32351205.
  10. ^ "Form 10-K" (PDF). Merck & Co., Inc. Archived from the original (PDF) on 2011-08-05. Retrieved 2011-05-03.
[edit]
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