Esmirtazapine: Difference between revisions

Esmirtazapine
Clinical data
Routes of; administration	Oral
ATC code	none;
Legal status
Legal status	In general: uncontrolled;
Pharmacokinetic data
Metabolism	Liver (CYP2D6)
Elimination half-life	10 hours
Identifiers
	IUPAC name (S)-1,2,3,4,10,14b-hexahydro-2-methylpyrazino(2,1-a)pyrido(2,3-c)(2)benzazepine;
CAS Number	61337-87-9 ;
PubChem CID	3085218; E. maleate: 6451144;
DrugBank	DB06678 ;
ChemSpider	2342166 ;
UNII	4685R51V7M;
KEGG	D04055 ;
CompTox Dashboard (EPA)	DTXSID001029320 ;
ECHA InfoCard	100.056.994
Chemical and physical data
Formula	C17H19N3
Molar mass	265.360 g·mol−1
3D model (JSmol)	Interactive image;
Melting point	114 to 116 °C (237 to 241 °F)
Solubility in water	Soluble in methanol and chloroform
	SMILES CN1CCN2c3c(cccn3)Cc4ccccc4[C@H]2C1;
	InChI 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 ; Key:RONZAEMNMFQXRA-MRXNPFEDSA-N ;
	(what is this?) (verify)

Browse history interactively

← Previous edit

Content deleted Content added

VisualWikitext

Inline

Latest revision as of 14:56, 29 February 2024

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-HT_2A 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]

References

^ ^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.
^ 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.
^ ^a ^b "Future Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD". Neurotransmitter.net.
^ Clinical trial number NCT00561574 for "A Long-Term Safety Study of Org 50081 in Elderly Outpatients With Chronic Primary Insomnia (176005)" at ClinicalTrials.gov
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ "Form 10-K" (PDF). Merck & Co., Inc. Archived from the original (PDF) on 2011-08-05. Retrieved 2011-05-03.

External links

Media related to Esmirtazapine at Wikimedia Commons

[insommnia-1] 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.

[urlwww.page-meeting.org-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.

[urlFuture_Treatments_for_Depression,_Anxiety,_Sleep_Disorders,_Psychosis,_and_ADHD_--_Neurotransmitter.net-3] "Future Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD". Neurotransmitter.net.

[NCT00561574-4] Clinical trial number NCT00561574 for "A Long-Term Safety Study of Org 50081 in Elderly Outpatients With Chronic Primary Insomnia (176005)" at ClinicalTrials.gov

[pmid18673166-5] 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.

[pmid19775194-6] 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.

[isbn0-521-88663-5-7] 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.

[2]

[1]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

@@ Line 1: / Line 1: @@
+{{Short description|Drug formerly under development for treatment of menopause symptoms}}
 {{Drugbox
 | Verifiedfields = changed
@@ Line 10: / Line 11: @@
 | pregnancy_category =
 | legal_status = Uncontrolled
-| routes_of_administration = [[Mouth|Oral]]
+| routes_of_administration = [[Oral administration|Oral]]
 <!--Pharmacokinetic data-->
 | 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 | 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>
-| elimination_half-life =
 | excretion =
 <!--Identifiers-->
@@ Line 32: / Line 33: @@
 | PubChem = 3085218
 | DrugBank_Ref = {{drugbankcite|changed|drugbank}}
-| DrugBank = DB00316
+| DrugBank = DB06678
 <!--Chemical data-->
 | C=17 | H=19 | N=3
-| molecular_weight = 265.35 g/mol
 | smiles = CN1CCN2c3c(cccn3)Cc4ccccc4[C@H]2C1
 | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
@@ Line 44: / Line 44: @@
 | melting_high = 116
 | solubility = Soluble in [[methanol]] and [[chloroform]]
+| sol_units = &nbsp;
 }}
-'''Esmirtazapine''' ('''ORG-50,081''') is a [[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 | work = | accessdate = }}</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 web | 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 | format = | work = | accessdate = }}</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| url = }}</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 | url = http://informahealthcare.com/doi/abs/10.1185/03007990903240519}}</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 | pages = | isbn = 0-521-88663-5 | oclc = | doi = | url = https://books.google.com/books?id=zqvVZOea2JAC&lpg=PA112&dq=esmirtazapine&pg=PA112#v=onepage&q=&f=false}}</ref>  As of March 2010, Merck terminated internal clinical development program for esmirtazapine, for hot flashes and insomnia, for strategic reasons.<ref>http://www.merck.com/investors/financials/form-10-K-2009-final.pdf</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&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=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 ==
@@ Line 52: / Line 57: @@
 == References ==
-{{Reflist}}
+{{Reflist|2}}
+== External links ==
+*{{Commons category-inline}}
 {{Antidepressants}}
 {{Hypnotics}}
+{{Navboxes
+| title = [[Pharmacodynamics]]
+| titlestyle = background:#ccccff
+| list1 =
 {{Adrenergic receptor modulators}}
 {{Histamine receptor modulators}}
 {{Serotonin receptor modulators}}
+}}
-{{Tricyclics}}
+{{Tetracyclics}}
-[[Category:Enantiopure drugs]]
 [[Category:Alpha-2 blockers]]
+[[Category:Enantiopure drugs]]
 [[Category:H1 receptor antagonists]]
+[[Category:Drugs developed by Schering-Plough]]
+[[Category:Drugs developed by Merck & Co.]]
 [[Category:Noradrenergic and specific serotonergic antidepressants]]
-[[Category:Serotonin antagonists]]
+[[Category:Serotonin receptor antagonists]]
 [[Category:Tetracyclic antidepressants]]
+[[Category:Abandoned drugs]]
-{{nervous-system-drug-stub}}
-{{Organic-compound-stub}}

v t e Tetracyclics
Classes	Polyketides Tetracenes Steroids
Antibiotics	Tetracyclines Tetracycline Chlortetracycline Demeclocycline Doxycycline Eravacycline Lymecycline Minocycline Omadacycline Oxytetracycline Rolitetracycline Sarecycline Glycylcyclines Tigecycline Triterpenes Fusidanes Fusidic acid Helvolic acid Cephalosporin P₁
Antidepressants (TeCAs)	Azipramine Ciclopramine Esmirtazapine Mianserin Mirtazapine Naranol Oxaprotiline Setiptiline
Steroids	Gonanes Steranes Cholane Cholestane Ergostane Sex hormone steroids Androstanes Androstenediol Dehydroepiandrosterone Testosterone Estranes Estetrol Estradiol Estriol Estrone Pregnanes Progestogens Progesterone Progestins Acetomepregenol Chlormadinone acetate Danazol Delmadinone acetate Etonogestrel Gestodene Hydroxyprogesterone caproate Levonorgestrel Norethisterone Norgestrel Segesterone acetate Tibolone Corticosteroids Cortisone Cortisol Prednisone Prednisolone Aldosterone Allopregnanes Norpregnane Retropregnane Sterols Phytosterols Campesterol beta-Sitosterol Ergosterols Secosteroids Ergocalciferol Cholecalciferol Cholesterol Stanol esters Triterpenes Cycloartane Cucurbitacins Cucurbitane Dammarane Euphane Lanostane Protostane