Vortioxetine

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Vortioxetine
Vortioxetine.svg
Vortioxetine ball-and-stick model.png
Clinical data
Pronunciation /vɔːrtiˈɒksətn/ vor-tee-OK-sə-teen
Trade names Trintellix, Brintellix
Synonyms Lu AA21004
License data
Pregnancy
category
  • AU: B3 [1]
  • US: C (Risk not ruled out)
Routes of
administration
By mouth (film-coated tablets)
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 75% (peak at 7–11 hours)
Protein binding 98%
Metabolism Extensive hepatic, primarily CYP2D6-mediated oxidation
Elimination half-life 66 hours
Excretion 59% in urine, 26% in feces
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
Formula C18H22N2S
Molar mass 298.45 g/mol (379.36 as hydrobromide)
3D model (JSmol)
 NoYesY (what is this?)  (verify)

Vortioxetine[note 1] is an antidepressant medication that is prescribed to treat depression. It purportedly relieves depression symptoms by increasing serotonin concentrations in the brain, by inhibiting its reuptake in the synapse and by modulating (activating certain receptors while blocking, or antagonizing, others) certain serotonin receptors. This puts it in the class of atypical antidepressants known as serotonin modulators and stimulators. It is made by the pharmaceutical companies Lundbeck and Takeda.[2]

Medical uses[edit]

Vortioxetine is used as a treatment for major depressive disorder.[2][3][4][5]

Adverse effects[edit]

The most common side effects reported with vortioxetine are nausea, diarrhea, dry mouth, constipation, vomiting, flatulence, dizziness, and sexual dysfunction.[2] Vortioxetine used alone in high dose or in combination with other medications, such as other antidepressants, can produce a potentially life-threatening drug reaction known as serotonin syndrome.[2]

Incidence of sexual dysfunction is higher in patients taking vortioxetine than in people taking placebos but appears to be lower than in people taking most other antidepressants.[2][5]

Pharmacology[edit]

Vortioxetine's pKa values are determined to be 9.1 (± 0.1) and 3.0 (± 0.2) according to Australian Public Assessment Report for vortioxetine hydrobromide. [6]

Pharmacodynamics[edit]

Vortioxetine is a so-called serotonin modulator and stimulator.[7] It has been shown to possess the following pharmacological actions:[2][8][9][10][11]

Target Affinity Functional activity Action
Ki (nM) IC50 / EC50 (nM) IA (%)
SERT* 1.6 5.4 Inhibition
NET* 113 Inhibition
5-HT1A* 15 200 96 Agonist
5-HT1B* 33 120 55 Partial agonist
5-HT1D* 54 370 Antagonist
5-HT3* 3.7 12 Antagonist
5-HT7* 19 450 Antagonist
β1 46[8]

* Human isoforms

Pharmacokinetics[edit]

Vortioxetine reaches peak plasma concentration (Cmax) within 7 to 11 hours post-administration (Tmax), and its mean terminal half-life (​T1/2) is ≈ 66 hours. Steady-state plasma concentrations are typically reached within two weeks.[2] It has no active metabolites (i.e., it is not a prodrug).[2]

History[edit]

10 mg tablets of vortioxetine (Trintellix).

Vortioxetine was discovered by scientists at Lundbeck who reported the rationale and synthesis for the drug (then called Lu AA21004) in a 2011 paper.[8][12]

In 2007, the compound was in Phase II clinical trials, and Lundbeck and Takeda entered into a partnership in which Takeda paid Lundbeck $40 million upfront, with promises of up to $345 million in milestone payments, and Takeda agreed to pay most of the remaining cost of developing the drug. The companies agreed to co-promote the drug in the US and Japan, and that Lundbeck would receive a royalty on all such sales. The deal included another drug candidate, tedatioxetine (Lu AA24530), and could be expanded to include two other Lundbeck compounds.[13]

Vortioxetine was approved by the U.S. FDA for the treatment of major depressive disorder (MDD) in adults in September 2013,[14] and it was approved in Europe later that year.[15]

Vortioxetine was previously trademarked as Brintellix in the United States, but on May 2, 2016, the US FDA approved a name change to Trintellix in order to avoid confusion with the blood-thinning medication Brilinta (ticagrelor).[16]

Research[edit]

Vortioxetine has been studied in several clinical trials as a potential treatment for generalized anxiety disorder; however, it has not been shown to be clinically beneficial for this application.[17]

See also[edit]

Notes[edit]

  1. ^ trade names Trintellix (CA, US), Brintellix (EU, RU). During early development it was known as Lu AA21004.

References[edit]

  1. ^ "TGA eBS - Product and Consumer Medicine Information Licence". www.ebs.tga.gov.au. Archived from the original on 29 April 2018. Retrieved 29 April 2018. 
  2. ^ a b c d e f g h US Label Archived 2016-01-31 at the Wayback Machine. Last updated July 2014 after review in September, 2014. Versions of label are available at FDA index page Page accessed January 19, 2016
  3. ^ Connolly, KR; Thase, ME (2016). "Vortioxetine: a New Treatment for Major Depressive Disorder". Expert opinion on pharmacotherapy. 17 (3): 421–31. doi:10.1517/14656566.2016.1133588. PMID 26679430. The authors suggest that vortioxetine is currently a good second-line antidepressant option and shows promise, pending additional long-term data, to become a first-line antidepressant option. 
  4. ^ Köhler S, Cierpinsky K, Kronenberg G, Adli M. The serotonergic system in the neurobiology of depression: Relevance for novel antidepressants. J Psychopharmacol. 2016 Jan;30(1):13-22. doi:10.1177/0269881115609072 PMID 26464458
  5. ^ a b Kelliny M, Croarkin PE, Moore KM, Bobo WV. Profile of vortioxetine in the treatment of major depressive disorder: an overview of the primary and secondary literature. Ther Clin Risk Manag. 2015 Aug 12;11:1193-212. doi:10.2147/TCRM.S55313 PMID 26316764 Free full text Archived 2018-04-29 at the Wayback Machine.
  6. ^ "Australian Public Assessment Report for vortioxetine hydrobromide" (PDF). p. 11. Archived (PDF) from the original on 2017-08-01. Retrieved 2018-05-05. 
  7. ^ "Lundbeck's "Serotonin Modulator and Stimulator" Lu AA21004: How Novel? How Good? - GLG News". Archived from the original on 2011-07-24. 
  8. ^ a b c Bang-Andersen B, Ruhland T, Jørgensen M, et al. (May 2011). "Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder". Journal of Medicinal Chemistry. 54 (9): 3206–21. doi:10.1021/jm101459g. PMID 21486038. 
  9. ^ N. Moore; B. Bang-Andersen; L. Brennum; K. Fredriksen; S. Hogg; A. Mork; T. Stensbol; H. Zhong; C. Sanchez; D. Smith (August 2008). "Lu AA21004: a novel potential treatment for mood disorders". European Neuropsychopharmacology. 18 (Supplement 4): S321. doi:10.1016/S0924-977X(08)70440-1. Archived from the original on 2018-01-21. 
  10. ^ Sanchez, C; Asin, KE; Artigas, F (1 January 2015). "Vortioxetine, a Novel Antidepressant with Multimodal Activity: Review of Preclinical and Clinical Data". Pharmacology & Therapeutics. 145: 43–57. doi:10.1016/j.pharmthera.2014.07.001. ISSN 1879-016X. PMID 25016186. Retrieved 10 August 2016. 
  11. ^ Stahl, Stephen M. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications (4th ed.). Cambridge University Press. ISBN 978-1107686465. 
  12. ^ Sanchez, C; Asin, KE; Artigas, F (2015). "Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data". Pharmacol. Ther. 145: 43–57. doi:10.1016/j.pharmthera.2014.07.001. PMID 25016186. 
  13. ^ Daniel Beaulieu for First Word Pharma. September 5th, 2007 Lundbeck, Takeda enter strategic alliance for mood disorder, anxiety drugs Archived 2016-10-10 at the Wayback Machine.
  14. ^ FDA approves new drug to treat major depressive disorder Archived 2013-10-03 at the Wayback Machine., U.S. Food and Drug Administration Press Announcement.
  15. ^ EMA Brintellix page at EMA site Archived 2016-01-26 at the Wayback Machine. Page accessed January 19, 2016
  16. ^ Commissioner, Office of the. "Safety Alerts for Human Medical Products - Brintellix (vortioxetine): Drug Safety Communication - Brand Name Change to Trintellix, to Avoid Confusion With Antiplatelet Drug Brilinta (ticagrelor)". www.fda.gov. Archived from the original on 2016-05-05. Retrieved 2016-05-02. 
  17. ^ Fu, Jie; Peng, Lilei; Li, Xiaogang (2016-04-19). "The efficacy and safety of multiple doses of vortioxetine for generalized anxiety disorder: a meta-analysis". Neuropsychiatric Disease and Treatment. 12: 951–959. doi:10.2147/NDT.S104050. ISSN 1176-6328. PMC 4844447Freely accessible. PMID 27143896.