fbpx
Wikipedia

Samidorphan

March 14, 2024

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
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
CAS Number
  • 852626-89-2 Y
PubChem CID
  • 11667832
ChemSpider
  • 23259667
UNII
  • 7W2581Z5L8
KEGG
  • D10162 Y
Chemical and physical data
FormulaC21H26N2O4
Molar mass370.449 g·mol−1
3D model (JSmol)
  • Interactive image
  • 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 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 edit

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 μ-opioid receptor (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 edit

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

Pharmacology edit

Pharmacodynamics edit

Samidorphan at the opioid receptors[18][19]
Receptor Ki EC50 Emax IC50 Imax
MORTooltip mu-Opioid receptor 0.052 nM – 3.8% 0.88 nM 92%
KORTooltip kappa-Opioid receptor 0.23 nM 3.3 nM 36% 38 nM 57%
DORTooltip 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 edit

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

Chemistry edit

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

References edit

  1. ^ 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.
  2. ^ 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.
  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. ^ 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.
  6. ^ Paik J (August 2021). "Olanzapine/Samidorphan: First Approval". Drugs. 81 (12): 1431–1436. doi:10.1007/s40265-021-01568-0. PMID 34304374. 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. ^ 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.
  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. ^ 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.
  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. ^ 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.
  19. ^ 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.
  20. ^ 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.
  21. ^ 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.

External links edit

  • Buprenorphine/samidorphan (ALKS-5461 - AdisInsight
  • Olanzapine/samidorphan (ALKS-3831) - AdisInsight

March 14, 2024
samidorphan, inntooltip, international, nonproprietary, name, usantooltip, united, states, adopted, name, developmental, code, names, alks, 0313, opioid, antagonist, that, form, olanzapine, samidorphan, brand, name, lybalvi, used, treatment, schizophrenia, bip. 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 SamidorphanClinical dataOther namesALKS 33 RDC 0313 3 Carboxamido 4 hydroxynaltrexoneRoutes ofadministrationOralPharmacokinetic dataElimination half life7 9 hours 1 2 IdentifiersIUPAC name 17 Cyclopropylmethyl 4 14 dihydroxy 6 oxomorphinan 3 carboxamideCAS Number852626 89 2 YPubChem CID11667832ChemSpider23259667UNII7W2581Z5L8KEGGD10162 YChemical and physical dataFormulaC 21H 26N 2O 4Molar mass370 449 g mol 13D model JSmol Interactive imageSMILES c1cc c c2c1C C H 3 C 4 C 2 CCN3CC5CC5 CC O CC4 O O C O NInChI 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 s1Key RYIDHLJADOKWFM MAODMQOUSA NSamidorphan 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 Contents 1 Development 2 Side effects 3 Pharmacology 3 1 Pharmacodynamics 3 2 Pharmacokinetics 4 Chemistry 5 References 6 External linksDevelopment 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 m opioid receptor MOR weak partial agonist and k 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 editSide effects of samidorphan include somnolence and gastrointestinal disturbances among others 1 Pharmacology editPharmacodynamics edit Samidorphan at the opioid receptors 18 19 Receptor Ki EC50 Emax IC50 ImaxMORTooltip mu Opioid receptor 0 052 nM 3 8 0 88 nM 92 KORTooltip kappa Opioid receptor 0 23 nM 3 3 nM 36 38 nM 57 DORTooltip 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 m opioid receptor MOR and to a lesser extent as a partial agonist of the k opioid receptor KOR and d 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 edit The 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 amp 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 amp 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 amp Medicinal Chemistry Letters 15 8 2107 10 doi 10 1016 j bmcl 2005 02 032 PMID 15808478 External links editBuprenorphine samidorphan ALKS 5461 AdisInsight Olanzapine samidorphan ALKS 3831 AdisInsight Retrieved from https en wikipedia org w index php title Samidorphan amp oldid 1203095627, wikipedia, wiki, book, books, library,

article

, read, download, free, free download, mp3, video, mp4, 3gp, jpg, jpeg, gif, png, picture, music, song, movie, book, game, games.