Viloxazine

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Viloxazine
Viloxazine structure.svg
Viloxazine molecule spacefill.png
Clinical data
Trade namesQelbree, Vivalan, Emovit, others
Other namesSPN-812
License data
Routes of
administration
By mouth
Drug classAntidepressant; Norepinephrine reuptake inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding76–82%[1]
MetabolismHydroxylation (CYP2D6), glucuronidation (UGT1A9, UGT2B15)[1]
Metabolites5-Hydroxyviloxazine glucuronide[1]
Elimination half-lifeIR: 2–5 hours[2]
ER: 7.02 ± 4.74 hours[1]
ExcretionUrine (~90%), feces (<1%)[1][3]
Identifiers
  • (RS)-2-[(2-ethoxyphenoxy)methyl]morpholine[4]
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.051.148 Edit this at Wikidata
Chemical and physical data
FormulaC13H19NO3
Molar mass237.299 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • CCOC1=CC=CC=C1OCC1CNCCO1

  • as HCl: Cl.CCOC1=CC=CC=C1OCC1CNCCO1
  • InChI=1S/C13H19NO3/c1-2-15-12-5-3-4-6-13(12)17-10-11-9-14-7-8-16-11/h3-6,11,14H,2,7-10H2,1H3 checkY
  • Key:YWPHCCPCQOJSGZ-UHFFFAOYSA-N checkY

  • as HCl: InChI=1S/C13H19NO3.ClH/c1-2-15-12-5-3-4-6-13(12)17-10-11-9-14-7-8-16-11;/h3-6,11,14H,2,7-10H2,1H3;1H
  • Key:HJOCKFVCMLCPTP-UHFFFAOYSA-N
 ☒NcheckY (what is this?)  (verify)

Viloxazine, sold under the brand name Qelbree among others, is a medication which is used in the treatment of attention deficit hyperactivity disorder (ADHD) in children and depression.[1][5] It was marketed for more than two decades as an antidepressant in Europe before being repurposed as a treatment for ADHD and launched in the United States in April 2021.[5][1][6][7] Viloxazine is taken by mouth.[1]

Viloxazine acts as a selective norepinephrine reuptake inhibitor (NRI).[1][5] However, it may also act as an antagonist of the serotonin 5-HT2B receptor and as an agonist of the serotonin 5-HT2C receptors, actions which may be involved in its therapeutic effects.[8][5]

Medical uses[edit]

Viloxazine is indicated to treat attention deficit hyperactivity disorder (ADHD) in people aged six through seventeen.[1] It was previously marketed as an antidepressant for the treatment of major depressive disorder;[5] and is proven to be effective in mild to moderate as well as severe depression with or without co-morbid symptoms.[9]

Available forms[edit]

Viloxazine is available for ADHD in the form of 100, 150, and 200 mg extended-release capsules.[1] These capsules can be opened and sprinkled into food for easier administration.[1]

Side effects[edit]

Side effects included nausea, vomiting, insomnia, loss of appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipation, vertigo, orthostatic hypotension, edema of the lower extremities, dysarthria, tremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, seizure, (there were three cases worldwide, and most animal studies [and clinical trials that included epilepsy patients] indicated the presence of anticonvulsant properties, so was not completely contraindicated in epilepsy[10]) and increased libido.[11]

Interactions[edit]

Viloxazine increased plasma levels of phenytoin by an average of 37%.[12] It also was known to significantly increase plasma levels of theophylline and decrease its clearance from the body,[13] sometimes resulting in accidental overdose of theophylline.[14]

Pharmacology[edit]

Mechanism of action[edit]

Viloxazine, like imipramine, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, it did not block reuptake of norepinephrine in either the medullae or the hypothalami of rats. As for serotonin, while its reuptake inhibition was comparable to that of desipramine (i.e., very weak), viloxazine did potentiate serotonin-mediated brain functions in a manner similar to amitriptyline and imipramine, which are relatively potent inhibitors of serotonin reuptake.[15] Unlike any of the other drugs tested, it did not exhibit any anticholinergic effects.[15]

More recent research has found that the mechanism of action of viloxazine may be more complex than previously assumed.[8] It appears to act as a potent antagonist of 5-HT2B receptors and as a potent agonist of 5-HT2C receptors.[8] These actions may be involved in its effectiveness for ADHD.[8]

It has also been found to up-regulate GABAB receptors in the frontal cortex of rats.[16]

Pharmacodynamics[edit]

The affinities (KD) of viloxazine at the human monoamine transporters are 155–630 nM for the norepinephrine transporter (NET), 17,300 nM for the serotonin transporter (SERT), and >100,000 nM for the dopamine transporter (DAT).[17][8] As such, viloxazine is a highly selective norepinephrine reuptake inhibitor (NRI).[17][8] Viloxazine has negligible affinity for a variety of assessed receptors, including the serotonin 5-HT1A and 5-HT2A receptors, the dopamine D2 receptor, the α1- and α2-adrenergic receptors, the histamine H1 receptor, and the muscarinic acetylcholine receptors (all >10,000 nM).[18][19] The binding of viloxazine to other receptors has also been assessed.[8] In 2020, viloxazine was reported to have significant affinity for the serotonin 5-HT2B and 5-HT2C receptors (Ki = 3,900 nM and 6,400 nM) and to act as an antagonist and agonist of these receptors, respectively.[8][5] It also showed weak antagonistic activity at the serotonin 5-HT7 receptor and the α1B- and β2-adrenergic receptors.[8][5]

Pharmacokinetics[edit]

The bioavailability of extended-release viloxazine relative to an instant-release formulation was about 88%.[1] Peak and AUC levels of extended-release viloxazine are proportional over a dosage range of 100 to 400 mg once daily.[1] The time to peak levels is 5 hours with a range of 3 to 9 hours after a single 200 mg dose.[1] A high-fat meal modestly decreases levels of viloxazine and delays the time to peak by about 2 hours.[1] Steady-state levels of viloxazine are released after 2 days of once-daily administration and no accumulation occurs.[1] Levels of viloxazine are approximately 40 to 50% higher in children age 6 to 11 years compared to children age 12 to 17 years.[1]

The plasma protein binding of viloxazine is 76 to 82% over a concentration range of 0.5 to 10 μg/mL.[1] The metabolism of viloxazine is primarily via the cytochrome P450 enzyme CYP2D6 and the UDP-glucuronosyltransferases UGT1A9 and UGT2B15.[1] The major metabolite of viloxazine is 5-hydroxyviloxazine glucuronide.[1] Viloxazine levels are slightly higher in CYP2D6 poor metabolizers relative to CYP2D6 extensive metabolizers.[1] The elimination of viloxazine is mainly renal.[1] Approximately 90% of the dose is excreted in urine within 24 hours and less than 1% of the dose is recovered in feces.[1] The elimination half-life of instant-release viloxazine is 2 to 5 hours (2–3 hours in the most reliable studies)[2] and the half-life of extended-release viloxazine is 7.02 ± 4.74 hours.[1]

Chemistry[edit]

Viloxazine is a racemic compound with two stereoisomers, the (S)-(–)-isomer being five times as pharmacologically active as the (R)-(+)-isomer.[20]

History[edit]

Viloxazine was discovered by scientists at Imperial Chemical Industries when they recognized that some beta blockers inhibited serotonin reuptake inhibitor activity in the brain at high doses. To improve the ability of their compounds to cross the blood brain barrier, they changed the ethanolamine side chain of beta blockers to a morpholine ring, leading to the synthesis of viloxazine.[21]: 610[22]: 9 The drug was first marketed in 1976.[23] It was never approved by the FDA,[24] but the FDA granted it an orphan designation (but not approval) for cataplexy and narcolepsy in 1984.[25] It was withdrawn from markets worldwide in 2002 for business reasons.[21][26]

As of 2015, Supernus Pharmaceuticals was developing extended release formulations of viloxazine as a treatment for ADHD and major depressive disorder under the names SPN-809 and SPN-812.[27][28]

Research[edit]

Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine.[29][30] By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.[31]

In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM[32] without really improving daytime somnolence.[33]

In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy.[26]

Viloxazine has also been studied for the treatment of alcoholism, with some success.[34]

While viloxazine may have been effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia.[35]

References[edit]

  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 "Qelbree- viloxazine hydrochloride capsule, extended release". DailyMed. Retrieved 1 June 2021.
  2. ^ a b Pinder RM, Brogden RN, Speight TM, Avery GS (June 1977). "Viloxazine: a review of its pharmacological properties and therapeutic efficacy in depressive illness". Drugs. 13 (6): 401–21. doi:10.2165/00003495-197713060-00001. PMID 324751. S2CID 44804763.
  3. ^ Case DE, Reeves PR (February 1975). "The disposition and metabolism of I.C.I. 58,834 (viloxazine) in humans". Xenobiotica. 5 (2): 113–29. doi:10.3109/00498257509056097. PMID 1154799.
  4. ^ "SID 180462-- PubChem Substance Summary". Retrieved 5 November 2005.
  5. ^ a b c d e f g Cutler AJ, Mattingly GW, Jain R, O'Neal W (October 2020). "Current and future nonstimulants in the treatment of pediatric ADHD: monoamine reuptake inhibitors, receptor modulators, and multimodal agents". CNS Spectr: 1–9. doi:10.1017/S1092852920001984. PMID 33121553.
  6. ^ "Qelbree: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 2 April 2021.
  7. ^ "Supernus Announces FDA Approval of Qelbree (SPN-812) for the Treatment of ADHD". Supernus Pharmaceuticals (Press release). 2 April 2021. Retrieved 3 April 2021.
  8. ^ a b c d e f g h i Yu, Chungping; Garcia-Olivares, Jennie; Candler, Shawn; Schwabe, Stefan; Maletic, Vladimir (2020). "New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties". Journal of Experimental Pharmacology. 12: 285–300. doi:10.2147/JEP.S256586. ISSN 1179-1454. PMC 7473988. PMID 32943948.
  9. ^ Findling, Robert L.; Candler, Shawn A.; Nasser, Azmi F.; Schwabe, Stefan; Yu, Chungping; Garcia-Olivares, Jennie; O’Neal, Welton; Newcorn, Jeffrey H. (2021-05-18). "Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status". CNS Drugs. Springer Science and Business Media LLC. doi:10.1007/s40263-021-00825-w. ISSN 1172-7047.
  10. ^ Edwards JG, Glen-Bott M (September 1984). "Does viloxazine have epileptogenic properties?". Journal of Neurology, Neurosurgery, and Psychiatry. 47 (9): 960–4. doi:10.1136/jnnp.47.9.960. PMC 1027998. PMID 6434699.
  11. ^ Chebili S, Abaoub A, Mezouane B, Le Goff JF (1998). "Antidepressants and sexual stimulation: the correlation" [Antidepressants and sexual stimulation: the correlation]. L'Encéphale (in French). 24 (3): 180–4. PMID 9696909.
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  13. ^ Perault MC, Griesemann E, Bouquet S, Lavoisy J, Vandel B (September 1989). "A study of the interaction of viloxazine with theophylline". Therapeutic Drug Monitoring. 11 (5): 520–2. doi:10.1097/00007691-198909000-00005. PMID 2815226.
  14. ^ Laaban JP, Dupeyron JP, Lafay M, Sofeir M, Rochemaure J, Fabiani P (1986). "Theophylline intoxication following viloxazine induced decrease in clearance". European Journal of Clinical Pharmacology. 30 (3): 351–3. doi:10.1007/BF00541543. PMID 3732375. S2CID 10114046.
  15. ^ a b Lippman W, Pugsley TA (August 1976). "Effects of viloxazine, an antidepressant agent, on biogenic amine uptake mechanisms and related activities". Canadian Journal of Physiology and Pharmacology. 54 (4): 494–509. doi:10.1139/y76-069. PMID 974878.
  16. ^ Lloyd KG, Thuret F, Pilc A (October 1985). "Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock". The Journal of Pharmacology and Experimental Therapeutics. 235 (1): 191–9. PMID 2995646.
  17. ^ a b Tatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". Eur J Pharmacol. 340 (2–3): 249–58. doi:10.1016/s0014-2999(97)01393-9. PMID 9537821.
  18. ^ Richelson E, Nelson A (July 1984). "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro". J Pharmacol Exp Ther. 230 (1): 94–102. PMID 6086881.
  19. ^ Wander TJ, Nelson A, Okazaki H, Richelson E (December 1986). "Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro". Eur J Pharmacol. 132 (2–3): 115–21. doi:10.1016/0014-2999(86)90596-0. PMID 3816971.
  20. ^ Danchev ND, Rozhanets VV, Zhmurenko LA, Glozman OM, Zagorevskiĭ VA (May 1984). "Behavioral and radioreceptor analysis of viloxazine stereoisomers" [Behavioral and radioreceptor analysis of viloxazine stereoisomers]. Biulleten' Eksperimental'noĭ Biologii I Meditsiny (in Russian). 97 (5): 576–8. PMID 6326891.
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  23. ^ Olivier B, Soudijn W, van Wijngaarden I (2000). "Serotonin, dopamine and norepinephrine transporters in the central nervous system and their inhibitors". Prog Drug Res. 54: 59–119. doi:10.1007/978-3-0348-8391-7_3. ISBN 978-3-0348-9546-0. PMID 10857386.
  24. ^ Dahmen, MM, Lincoln, J, and Preskorn, S. NARI Antidepressants, pp 816-822 in Encyclopedia of Psychopharmacology, Ed. Ian P. Stolerman. Springer-Verlag Berlin Heidelberg, 2010. ISBN 9783540687061
  25. ^ FDA. Orphan Drug Designations and Approvals: Viloxazine Page accessed August 1, 2-15
  26. ^ a b Vignatelli L, D'Alessandro R, Candelise L (2008). "Antidepressant drugs for narcolepsy". Cochrane Database Syst Rev (1): CD003724. doi:10.1002/14651858.CD003724.pub3. PMID 18254030.
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  28. ^ Supernus. Psychiatry portfolio Page accessed August 1, 2015
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  30. ^ ^ Yurdakök M, Kinik E, Güvenç H, Bedük Y (1987). "Viloxazine versus imipramine in the treatment of enuresis". The Turkish Journal of Pediatrics. 29 (4): 227–30. PMID 3332732.
  31. ^ Libert MH (1990). "The use of viloxazine in the treatment of primary enuresis" [The use of viloxazine in the treatment of primary enuresis]. Acta Urologica Belgica (in French). 58 (1): 117–22. PMID 2371930.
  32. ^ Guilleminault C, Mancuso J, Salva MA, et al. (1986). "Viloxazine hydrochloride in narcolepsy: a preliminary report". Sleep. 9 (1 Pt 2): 275–9. doi:10.1093/sleep/9.1.275. PMID 3704453.
  33. ^ Mitler MM, Hajdukovic R, Erman M, Koziol JA (January 1990). "Narcolepsy". Journal of Clinical Neurophysiology. 7 (1): 93–118. doi:10.1097/00004691-199001000-00008. PMC 2254143. PMID 1968069.
  34. ^ Altamura AC, Mauri MC, Girardi T, Panetta B (1990). "Alcoholism and depression: a placebo controlled study with viloxazine". International Journal of Clinical Pharmacology Research. 10 (5): 293–8. PMID 2079386.
  35. ^ Mattingly, GW; Anderson, RH (December 2016). "Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems". CNS Spectrums. 21 (S1): 45–59. doi:10.1017/S1092852916000808. PMID 28044946. S2CID 24310209.

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