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]
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Clinical data | |
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Other names | ALKS-33; RDC-0313; 3-Carboxamido-4-hydroxynaltrexone |
Routes of administration | Oral |
Pharmacokinetic data | |
Elimination half-life | 7–9 hours[1][2] |
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Chemical and physical data | |
Formula | C21H26N2O4 |
Molar mass | 370.449 g·mol−1 |
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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
editSamidorphan 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
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
editSide effects of samidorphan include somnolence and gastrointestinal disturbances among others.[1]
Pharmacology
editPharmacodynamics
editReceptor | 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
Pharmacokinetics
editThe elimination half-life of samidorphan is 7 to 9 hours.[1][2]
Chemistry
editSamidorphan has its origins in academia where 8-carboxamidocyclazocine and naltrexone were utilized in its design and synthesis.[21]
References
edit- ^ a b c d e f Chaudhary AM, Khan MF, Dhillon SS, Naveed S (July 2019). "A Review of Samidorphan: A Novel Opioid Antagonist". Cureus. 11 (7): e5139. doi:10.7759/cureus.5139. PMC 6741386. PMID 31523568.
- ^ a b Turncliff R, DiPetrillo L, Silverman B, Ehrich E (February 2015). "Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers". Clinical Therapeutics. 37 (2): 338–348. doi:10.1016/j.clinthera.2014.10.001. PMID 25456560.
- ^ a b "LYBALVI: Highlight of Prescribing Information" (PDF). U.S. Food and Drug Administration.
- ^ "Olanzapine/samidorphan - Alkermes plc". Adis Insight. Springer Nature Switzerland AG.
- ^ Citrome L, Graham C, Simmons A, Jiang Y, Todtenkopf MS, Silverman B, et al. (2021). "An Evidence-Based Review of OLZ/SAM for Treatment of Adults with Schizophrenia or Bipolar I Disorder". Neuropsychiatric Disease and Treatment. 17: 2885–2904. doi:10.2147/NDT.S313840. PMC 8437420. PMID 34526769.
- ^ Paik J (August 2021). "Olanzapine/Samidorphan: First Approval". Drugs. 81 (12): 1431–1436. doi:10.1007/s40265-021-01568-0. PMID 34304374. S2CID 236215923.
- ^ "Samidorphan". Adis Insight. Springer Nature Switzerland AG.
- ^ "Buprenorphine/samidorphan - Alkermes". Adis Insight. Springer Nature Switzerland AG.
- ^ "Baclofen/samidorphan". Adis Insight. Springer Nature Switzerland AG.
- ^ Hillemacher T, Heberlein A, Muschler MA, Bleich S, Frieling H (August 2011). "Opioid modulators for alcohol dependence". Expert Opinion on Investigational Drugs. 20 (8): 1073–1086. doi:10.1517/13543784.2011.592139. PMID 21651459. S2CID 43338618.
- ^ 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
- ^ "ALKS 5461 drug found to reduce depressive symptoms in Phase 1/2 study". 30 May 2012.
- ^ "Investigational ALKS 5461 Channels 'Opium Cure' for Depression".
- ^ LaMattina J (15 January 2013). "Will Alkermes' Antipsychotic ALKS-3831 Become Another Tredaptive?". Forbes.
- ^ Correll CU, Newcomer JW, Silverman B, DiPetrillo L, Graham C, Jiang Y, et al. (December 2020). "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. doi:10.1176/appi.ajp.2020.19121279. PMID 32791894. S2CID 221122225.
- ^ "Lybalvi: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 1 June 2021.
- ^ Ergenzinger, Ed. "New Antipsychotic Combo for Bipolar Disorder Approved by FDA | Psychology Today". www.psychologytoday.com. Retrieved 2021-07-24.
- ^ a b 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.
- ^ a b Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, et al. (April 2009). "Syntheses of novel high affinity ligands for opioid receptors". Bioorganic & Medicinal Chemistry Letters. 19 (8): 2289–2294. doi:10.1016/j.bmcl.2009.02.078. PMC 2791460. PMID 19282177.
- ^ McElroy SL, Guerdjikova AI, Blom TJ, Crow SJ, Memisoglu A, Silverman BL, Ehrich EW (April 2013). "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. doi:10.1002/eat.22114. PMID 23381803.
- ^ Wentland MP, Lu Q, Lou R, Bu Y, Knapp BI, Bidlack, JM (April 2005). "Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone". Bioorganic & Medicinal Chemistry Letters. 15 (8): 2107–10. doi:10.1016/j.bmcl.2005.02.032. PMID 15808478.