Chemistry:Samidorphan

From HandWiki
Short description: Opioid antagonist
Samidorphan
Samidorphan structure.svg
Clinical data
Other namesALKS-33; RDC-0313; 3-Carboxamido-4-hydroxynaltrexone
Routes of
administration		Oral
Pharmacokinetic data
Elimination half-life7–9 hours[1][2]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC21H26N2O4
Molar mass370.449 g·mol−1
3D model (JSmol)

Samidorphan (INN, USAN) (developmental code names ALKS-33, RDC-0313) is an opioid antagonist that in the form of olanzapine/samidorphan (brand name Lybalvi) is used in the treatment of schizophrenia and bipolar disorder.[1][3][4] Samidorphan reduces the weight gain associated with olanzapine.[5][6] Samidorphan is taken by mouth.[1][3]

Samidorphan was under development as a standalone medication for various indications but has been discontinued.[7] Buprenorphine/samidorphan for the treatment of major depressive disorder was rejected by the Food and Drug Administration due to insufficient evidence of effectiveness but remains in preregistration as of September 2021.[8] Development of baclofen/samidorphan has also been discontinued.[9]

Development

Samidorphan has been investigated for the treatment of alcoholism and cocaine addiction by its developer, Alkermes,[10][11] showing similar efficacy to naltrexone but possibly with reduced side effects.

However, it has attracted much more attention as part of the combination product ALKS-5461 (buprenorphine/samidorphan), where samidorphan is combined with the mixed MOR weak partial agonist and κ-opioid receptor (KOR) antagonist buprenorphine, as an antidepressant. Buprenorphine has shown antidepressant effects in some human studies, thought to be because of its antagonist effects at the KOR, but has not been further developed for this application because of its MOR agonist effects and consequent abuse potential. By combining buprenorphine with samidorphan to block the MOR agonist effects, the combination acts more like a selective KOR antagonist, and produces only antidepressant effects, without typical MOR effects such as euphoria or substance dependence being evident.[12][13]

Samidorphan was also studied in combination with olanzapine, as ALKS-3831 (olanzapine/samidorphan), for use in schizophrenia.[14] A Phase 3 study found that the addition of samidorphan to olanzapine significantly reduced weight gain compared to olanzapine alone,[15] and the combination was approved for the treatment of schizophrenia and bipolar disorder by the US Food and Drug Administration in May 2021, under the brand name Lybalvi.[16][17]

Side effects

Side effects of samidorphan include somnolence and gastrointestinal disturbances among others.[1]

Pharmacology

Pharmacodynamics

Samidorphan at the opioid receptors[18][19]
Receptor Ki EC50 Emax IC50 Imax
MOR 0.052 nM – 3.8% 0.88 nM 92%
KOR 0.23 nM 3.3 nM 36% 38 nM 57%
DOR 2.6 nM 1.5 nM 35% 6.9 nM 56%

Samidorphan acts primarily as an antagonist or very weak partial agonist of the μ-opioid receptor (MOR) and to a lesser extent as a partial agonist of the κ-opioid receptor (KOR) and δ-opioid receptor (DOR).[1][18][19] In accordance with this profile, samidorphan has been observed to produce some side effects that are potentially consistent with activation of the KOR such as somnolence, sedation, dizziness, and hallucinations in some patients in clinical trials.[20]

Pharmacokinetics

The elimination half-life of samidorphan is 7 to 9 hours.[1][2]

Chemistry

Samidorphan has its origins in academia where 8-carboxamidocyclazocine and naltrexone were utilized in its design and synthesis.[21]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "A Review of Samidorphan: A Novel Opioid Antagonist". Cureus 11 (7): e5139. July 2019. doi:10.7759/cureus.5139. PMID 31523568. 
  2. ↑ 2.0 2.1 "Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers". Clinical Therapeutics 37 (2): 338–348. February 2015. doi:10.1016/j.clinthera.2014.10.001. PMID 25456560. 
  3. ↑ 3.0 3.1 "LYBALVI: Highlight of Prescribing Information". U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213378s000lbl.pdf. 
  4. ↑ "Olanzapine/samidorphan - Alkermes plc". Adis Insight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800037287. 
  5. ↑ "An Evidence-Based Review of OLZ/SAM for Treatment of Adults with Schizophrenia or Bipolar I Disorder". Neuropsychiatric Disease and Treatment 17: 2885–2904. 2021. doi:10.2147/NDT.S313840. PMID 34526769. 
  6. ↑ "Olanzapine/Samidorphan: First Approval". Drugs 81 (12): 1431–1436. August 2021. doi:10.1007/s40265-021-01568-0. PMID 34304374. 
  7. ↑ "Samidorphan". Adis Insight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800029336. 
  8. ↑ "Buprenorphine/samidorphan - Alkermes". Adis Insight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800034331. 
  9. ↑ "Baclofen/samidorphan". Adis Insight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800025253. 
  10. ↑ "Opioid modulators for alcohol dependence". Expert Opinion on Investigational Drugs 20 (8): 1073–1086. August 2011. doi:10.1517/13543784.2011.592139. PMID 21651459. 
  11. ↑ Clinical trial number NCT01366001 for "ALK33BUP-101: Safety and Pharmacodynamic Effects of ALKS 33-BUP Administered Alone and When Co-administered With Cocaine" at ClinicalTrials.gov
  12. ↑ "ALKS 5461 drug found to reduce depressive symptoms in Phase 1/2 study". 30 May 2012. https://www.clinicaltrialsarena.com/uncategorized/newsalks-5461-reduce-depressive-study/. 
  13. ↑ "Investigational ALKS 5461 Channels 'Opium Cure' for Depression". http://infoviewer.biz/infodisplay/story/imn062020121658153330.html?APP=7&CU=imn5804. 
  14. ↑ LaMattina, John (15 January 2013). "Will Alkermes' Antipsychotic ALKS-3831 Become Another Tredaptive?". Forbes. https://www.forbes.com/sites/johnlamattina/2013/01/15/will-alkermes-antipsychotic-alks-3831-become-another-tredaptive/. 
  15. ↑ "Effects of Olanzapine Combined With Samidorphan on Weight Gain in Schizophrenia: A 24-Week Phase 3 Study". The American Journal of Psychiatry 177 (12): 1168–1178. December 2020. doi:10.1176/appi.ajp.2020.19121279. PMID 32791894. 
  16. ↑ "Lybalvi: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=213378. 
  17. ↑ Ergenzinger, Ed. "New Antipsychotic Combo for Bipolar Disorder Approved by FDA | Psychology Today" (in en). www.psychologytoday.com. https://www.psychologytoday.com/us/blog/night-sweats-and-delusions-grandeur/202106/new-antipsychotic-combo-bipolar-disorder-approved. 
  18. ↑ 18.0 18.1 Linda P. Dwoskin (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 398–399, 402–403. ISBN 978-0-12-420177-4. https://books.google.com/books?id=b3UpAgAAQBAJ&pg=PA398. 
  19. ↑ 19.0 19.1 "Syntheses of novel high affinity ligands for opioid receptors". Bioorganic & Medicinal Chemistry Letters 19 (8): 2289–2294. April 2009. doi:10.1016/j.bmcl.2009.02.078. PMID 19282177. 
  20. ↑ "A placebo-controlled pilot study of the novel opioid receptor antagonist ALKS-33 in binge eating disorder". The International Journal of Eating Disorders 46 (3): 239–245. April 2013. doi:10.1002/eat.22114. PMID 23381803. 
  21. ↑ "Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone". Bioorganic & Medicinal Chemistry Letters 15 (8): 2107–10. April 2005. doi:10.1016/j.bmcl.2005.02.032. PMID 15808478. 

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