Samidorphan

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Samidorphan
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
  • 17-(Cyclopropylmethyl)-4,14-dihydroxy-6-oxomorphinan-3-carboxamide
JSmol)
  • c1cc(c(c2c1C[C@@H]3[C@]4([C@]2(CCN3CC5CC5)CC(=O)CC4)O)O)C(=O)N
  • InChI=1S/C21H26N2O4/c22-19(26)15-4-3-13-9-16-21(27)6-5-14(24)10-20(21,17(13)18(15)25)7-8-23(16)11-12-1-2-12/h3-4,12,16,25,27H,1-2,5-11H2,(H2,22,26)/t16-,20-,21-/m1/s1
  • Key:RYIDHLJADOKWFM-MAODMQOUSA-N

Samidorphan (

INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name) (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

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

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

gastrointestinal disturbances among others.[1]

Pharmacology

Pharmacodynamics

Samidorphan at the opioid receptors[18][19]
Receptor Ki EC50 Emax IC50 Imax
MOR
Tooltip mu-Opioid receptor 		0.052 nM – 3.8% 0.88 nM 92%
KOR
Tooltip kappa-Opioid receptor 		0.23 nM 3.3 nM 36% 38 nM 57%
DOR
Tooltip delta-Opioid receptor 		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. ^
    PMID 31523568
    .
  2. ^
    PMID 25456560
    .
  3. ^ a b "LYBALVI: Highlight of Prescribing Information" (PDF). U.S. Food and Drug Administration.
  4. ^ "Olanzapine/samidorphan - Alkermes plc". Adis Insight. Springer Nature Switzerland AG.
  5. PMID 34526769
    .
  6. S2CID 236215923
    .
  7. ^ "Samidorphan". Adis Insight. Springer Nature Switzerland AG.
  8. ^ "Buprenorphine/samidorphan - Alkermes". Adis Insight. Springer Nature Switzerland AG.
  9. ^ "Baclofen/samidorphan". Adis Insight. Springer Nature Switzerland AG.
  10. S2CID 43338618
    .
  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.
  13. ^ "Investigational ALKS 5461 Channels 'Opium Cure' for Depression".
  14. ^ LaMattina J (15 January 2013). "Will Alkermes' Antipsychotic ALKS-3831 Become Another Tredaptive?". Forbes.
  15. S2CID 221122225
    .
  16. ^ "Lybalvi: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 1 June 2021.
  17. ^ Ergenzinger, Ed. "New Antipsychotic Combo for Bipolar Disorder Approved by FDA | Psychology Today". www.psychologytoday.com. Retrieved 2021-07-24.
  18. ^
    ISBN 978-0-12-420177-4
    .
  19. ^
    PMID 19282177
    .
  20. PMID 23381803
    .
  21. PMID 15808478
    .

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Samidorphan&oldid=1214709606"