Chemistry:Pimavanserin

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Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis.[1][2] It is taken by mouth.[1]

Side effects of pimavanserin include peripheral edema and confusion.[1] Unlike other antipsychotics, pimavanserin is not a dopamine receptor antagonist,[3] but rather is a selective antagonist or inverse agonist of the serotonin 5-HT2A receptor and to a lesser extent of the serotonin 5-HT2C receptor.[1]

Pimavanserin was first approved for medical use in 2016.[1] It was approved as a generic medication in 2024.[4]

Medical uses

Pimavanserin is used in the treatment of Parkinson's disease psychosis.[1]

Available forms

Pimavanserin is available in the form of 10 mg oral tablets and 34 mg oral capsules.[1]

Side effects

Side effects of pimavanserin include peripheral edema and confusion, among others.[1]

Pharmacology

Pharmacodynamics

Activities of pimavanserin
Target Affinity (Ki, nM)
5-HT1A ND
5-HT2A 0.087–0.5 (Ki)
1.9–50 (IC50)
5-HT2B 436 (Ki)
5-HT2C 0.44–10 (Ki)
91 (IC50)
D1–D5 300+
α1–β3 300+
H1–H4 300+
M1–M5 300+
σ1 120
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs:[5][6][1][7]

Pimavanserin acts as a selective inverse agonist or antagonist of the serotonin 5-HT2A receptor.[8][9][7][10] It is also an antagonist or inverse agonist of the serotonin 5-HT2C receptor to a lesser extent.[1]

The drug has an affinity (Ki) of 0.087 to 0.5 nM for the serotonin 5-HT2A receptor and 0.44 to 10 nM at the serotonin 5-HT2C receptor, whereas its functional inhibition (IC50) values have been reported to be 1.9 nM at the serotonin 5-HT2A receptor and 91 nM at the serotonin 5-HT2C receptor.[7][9] Hence, it shows 3- to 50-fold greater affinity for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor depending on the assay and 49-fold selectivity in terms of functional inhibition of the serotonin 5-HT2A receptor compared to the serotonin 5-HT2C receptor.[7]

Pimavanserin shows low binding to σ1 receptors (Ki = 120 nM) and has no appreciable affinity (Ki > 300 nM) to serotonin 5-HT2B, dopamine (including D2), muscarinic acetylcholine, histamine, or adrenergic receptors, or to calcium channels.[11][12]

Pharmacokinetics

Pimavanserin is slowsly absorbed and has a time to peak levels of 6 hours.[13][14][15] The elimination half-life of pimavanserin is 54 to 57 hours.[8][1] The half-life of its active metabolite N-desmethylpimavanserin is 200 hours.[1]

History

Development

Pimavanserin was developed by Acadia Pharmaceuticals.

Pimavanserin is expected to improve the effectiveness and side effect profile of antipsychotics.[16][17][18] The results of a clinical trial examining the efficacy, tolerability and safety of adjunctive pimavanserin to risperidone and haloperidol were published in November 2012, and the results showed that pimavanserin potentiated the antipsychotic effects of subtherapeutic doses of risperidone and improved the tolerability of haloperidol treatment by reducing the incidence of extrapyramidal symptoms.[19]

The drug met expectations for a Phase III clinical trial for the treatment of Parkinson's disease psychosis,[20] and has completed Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.[21]

In September 2014, the United States Food and Drug Administration (FDA) granted breakthrough therapy status to Acadia's New Drug Application for pimavanserin.[22]

FDA Approval

In April 2016, Nuplazid (pimavanserin) was approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis.[23][24] The non-binding advisory panel recommendation of 12-to-2 in support of approval that preceded the FDA approval action noted that the drug met an important need, despite its only providing modest benefits and posing serious safety issues.[25]

In June 2018, the FDA approved new dosages of pimavanserin to treat hallucinations and delusions associated with Parkinson's disease psychosis. A 34 mg capsule and 10 mg tablet formulation were approved. Previously, people were required to take two 17 mg tablets to achieve the recommended 34 mg dose per day. The 10 mg dose is indicated for people also taking CYP3A4 inhibitors (e.g., ketoconazole).[26]

HARMONY-Trial

In a Phase III, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov number NTC03325556) pimavanserin was given to people with dementia-related psychosis. The dementia was caused by Alzheimer's disease, dementia with lewy bodies, frontotemporal dementia, Parkinson's disease dementia, or vascular dementia. The trial was stopped early due to lack of efficacy. People treated with pimavanserin had a relapse in 13%, and those without 28%. Longer and larger trials are suggested.[27]

Controversy

In April 2018, CNN reported that some in the FDA were concerned that pimavanserin (Nuplazid) was "risky" when it was approved and noted there have been a substantial number of deaths reported by those using the drug. The story further noted that the drug was approved based on a "six-week study of about 200 patients".[28] The FDA began post-market monitoring of the drug to assess the validity of these claims.[29] In September 2018, the FDA stated their review "did not identify any new or unexpected safety findings with Nuplazid, or findings that are inconsistent with the established safety profile currently described in the drug label".[30]

Research

Pimavanserin was studied as a therapeutic agent in Phase III clinical trials for major depressive disorder and schizophrenia and Phase II trials for agitation. It was also under development for the treatment of insomnia, drug-induced akathisia, and drug-induced dyskinesia, but development for these indications was discontinued.[2]

In March 2024, Acadia Pharmaceuticals announced its decision to stop any further clinical trials of pimavanserin after the drug did not improve negative symptoms of schizophrenia better than placebo.[31]

As of November 2024, a phase 2 clinical trial is underway assessing the ability of pimavanserin to block the effects of the serotonergic psychedelic psilocybin.[32]

See also

  • Serotonin 5-HT2A receptor antagonist

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 "Highlights of prescribing information - NUPLAZID". https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/210793s009,207318s012lbl.pdf. 
  2. ↑ 2.0 2.1 "Pimavanserin - Acadia Pharmaceuticals - AdisInsight". http://adisinsight.springer.com/drugs/800014997. 
  3. ↑ "Pimavanserin: An Inverse Agonist Antipsychotic Drug". Journal of Psychosocial Nursing and Mental Health Services 54 (6): 21–4. June 2016. doi:10.3928/02793695-20160523-01. PMID 27245248. 
  4. ↑ "First-Time Generic Drug Approvals 2024". U.S. Food and Drug Administration. 8 March 2024. https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals. 
  5. ↑ "BindingDB BDBM139370 ACP-103::Nuplazid::Pimavanserin::Pimavanserin hydrochloride::Pimavanserin tartrate::US20230348421, Compound Pimavanserin::WO2023288027, Cmpd PIMA::bis(1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)-3-(4-(2-methylpropoxy)benzyl)urea) (2R,3R)-2,3-dihydroxybutanedioate". https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=139370. 
  6. ↑ "New and emerging treatments for schizophrenia: a narrative review of their pharmacology, efficacy and side effect profile relative to established antipsychotics". Neurosci Biobehav Rev 132: 324–361. January 2022. doi:10.1016/j.neubiorev.2021.11.032. PMID 34838528. PMC 7616977. https://kclpure.kcl.ac.uk/portal/en/publications/5ddc5d6a-81bb-413c-ad1a-a76177d49c97. 
  7. ↑ 7.0 7.1 7.2 7.3 "Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist". J Pharmacol Exp Ther 317 (2): 910–918. May 2006. doi:10.1124/jpet.105.097006. PMID 16469866. 
  8. ↑ 8.0 8.1 Cite error: Invalid <ref> tag; no text was provided for refs named Rev
  9. ↑ 9.0 9.1 "New antipsychotic drugs for the treatment of agitation and psychosis in Alzheimer's disease: focus on brexpiprazole and pimavanserin". F1000Res 9: 686. 2020. doi:10.12688/f1000research.22662.1. PMID 32695312. 
  10. ↑ "NUPLAZID Prescribing Information". 2018. https://www.nuplazid.com/pdf/NUPLAZID-Prescribing-Information-PI-v8-Sep-2018.pdf. 
  11. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Nuplazid FDA label
  12. ↑ "Mechanism of action of pimavanserin in Parkinson's disease psychosis: targeting serotonin 5HT2A and 5HT2C receptors". CNS Spectrums 21 (4): 271–275. August 2016. doi:10.1017/S1092852916000407. PMID 27503570. 
  13. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named MontiPandiPerumalWarrenSpence2018
  14. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Ancoli-IsraelCanoverWeiner2011
  15. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named VanoverRobbins-WeilertWilbraham2007
  16. ↑ "ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models". The Journal of Pharmacology and Experimental Therapeutics 322 (2): 862–70. August 2007. doi:10.1124/jpet.107.121715. PMID 17519387. 
  17. ↑ "A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model". Pharmacology Biochemistry and Behavior 90 (4): 540–4. October 2008. doi:10.1016/j.pbb.2008.04.010. PMID 18534670. 
  18. ↑ "Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders". Expert Opinion on Pharmacotherapy 9 (18): 3251–9. December 2008. doi:10.1517/14656560802532707. PMID 19040345. https://zenodo.org/record/1236273. 
  19. ↑ "Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day". Schizophrenia Research 141 (2–3): 144–52. November 2012. doi:10.1016/j.schres.2012.07.029. PMID 22954754. 
  20. ↑ "Treating Parkinson's Disease - Clinical Trial Pimavanserin". Acadia Pharmaceuticals. http://www.acadia-pharm.com/programs/parkinsons.htm. 
  21. ↑ "Acadia Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial" (Press release). Acadia Pharmaceuticals. 19 March 2007. Archived from the original on 7 November 2017. Retrieved 11 April 2009.
  22. ↑ "ACADIA Pharmaceuticals Receives FDA Breakthrough Therapy Designation for Nuplazid (Pimavanserin) for Parkinson's Disease Psychosis". Acadia Pharmaceuticals. 2 September 2014. http://news.acadia-pharm.com/phoenix.zhtml?c=125180&p=irol-newsArticle&ID=1962810&highlight=. 
  23. ↑ "FDA approves first drug to treat hallucinations and delusions associated with Parkinson's disease" (Press release). U.S. Food and Drug Administration. Archived from the original on 1 May 2016. Retrieved 1 May 2016.
  24. ↑ "Pimavanserin (Nuplazid): A Treatment for Hallucinations and Delusions Associated With Parkinson's Disease". P & T 42 (6): 368–371. June 2017. PMID 28579723. 
  25. ↑ "Gov't panel backs drug for Parkinson's". Beaver Dam Daily Citizen. Associated Press 105 (24): p. A8. 30 March 2016. https://www.newspapers.com/clip/40244145/gov_panel_backs_drug_for_parkinsons/. 
  26. ↑ "Acadia Pharmaceuticals Announces FDA Approval of New Dosing Formulation and Strength for NUPLAZID® (Pimavanserin)" (Press release). Acadia Pharmaceuticals. 29 June 2018. Retrieved 19 February 2019 – via Business Wire.
  27. ↑ "Trial of Pimavanserin in Dementia-Related Psychosis". The New England Journal of Medicine 385 (4): 309–319. July 2021. doi:10.1056/NEJMoa2034634. PMID 34289275. 
  28. ↑ "FDA worried drug was risky; now reports of deaths spark concern". CNN. 9 April 2018. https://www.cnn.com/2018/04/09/health/parkinsons-drug-nuplazid-invs/index.html. 
  29. ↑ "FDA re-examines safety of controversial new drug". CNN. https://www.cnn.com/2018/04/25/health/fda-nuplazid-safety-evaluation-invs/index.html. 
  30. ↑ "Drug Safety and Availability - FDA analysis finds no new or unexpected safety risks associated with Nuplazid (pimavanserin), a medication to treat the hallucinations and delusions of Parkinson's disease psychosis". https://www.fda.gov/Drugs/DrugSafety/ucm621160.htm. 
  31. ↑ "Acadia to Stop Trials Of Antipsychotic Drug After It Fails Schizophrenia Study" (in en). https://www.medscape.com/s/viewarticle/acadia-stop-trials-antipsychotic-drug-after-it-fails-2024a10004m5. 
  32. ↑ Psilocybin Mechanism of Action (MOA). 23 October 2024. https://clinicaltrials.gov/study/NCT06592833. Retrieved 13 November 2024. 



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