Chemistry:Pimavanserin

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Short description: Chemical compound
Pimavanserin
Pimavanserin structure.svg
Clinical data
Trade namesNuplazid
Other namesACP-103; BVF-036; BVF-048
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding94–97%[2]
MetabolismHepatic (CYP3A4, CYP3A5, CYP2J2)[1]
Elimination half-life54–56 hours[2]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC25H34FN3O2
Molar mass427.564 g·mol−1
3D model (JSmol)
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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 and is also being studied for the treatment of Alzheimer’s disease psychosis, schizophrenia, agitation, and major depressive disorder.[3] Unlike other antipsychotics, pimavanserin is not a dopamine receptor antagonist.[4]

Pharmacology

Pharmacodynamics

Pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT2A [5] receptors with high binding affinity (Ki 0.087 nM) and at serotonin 5-HT2C receptors with lower binding affinity (Ki 0.44 nM). 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.[1][6]

Pimavanserin has a unique mechanism of action relative to other antipsychotics, behaving as a selective inverse agonist of the serotonin 5-HT2A receptor, with 40-fold selectivity for this site over the 5-HT2C receptor and no significant affinity or activity at the 5-HT2B receptor or dopamine receptors.[2]

History

Development

Pimavanserin was developed by Acadia Pharmaceuticals.

Pimavanserin is expected to improve the effectiveness and side effect profile of antipsychotics.[7][8][9] 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.[10]

The drug met expectations for a Phase III clinical trial for the treatment of Parkinson's disease psychosis,[11] and has completed Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.[12]

In September 2014, the United States Food and Drug Administration (FDA) granted breakthrough therapy status to Acadia's New Drug Application for pimavanserin.[13]

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.[14][15] 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.[16]

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, patients were required to take two 17 mg tablets to achieve the recommenced 34 mg dose per day. The 10 mg dose is indicated for patients also taking CYP3A4 inhibitors (eg. ketoconazole).[17]

HARMONY-Trial

In a phase III, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov number NTC03325556) pimavanserin was applicated in patients with dementia-related psychosis. The dementia was caused by Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, Parkinson's disease with dementia, or vascular dementia. The trial was stopped early for efficacy. Patients treated with pimavanserin had a relapse in 13%, without in 28% (hazard ratio 0.35; 95% CI = 0.17-0.73; p = 0.005). Longer and larger trials are suggested.[18]

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".[19] The FDA began post-market monitoring of the drug to assess the validity of these claims.[20] 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".[21]

Research

Pimavanserin is under development for the treatment of major depressive disorder, schizophrenia, agitation, and psychiatric disorders.[3] As of March 2022, pimavanserin is in phase 3 clinical trials for major depressive disorder and schizophrenia, phase 2 trials for agitation, and phase 1 trials for psychiatric disorders.[3] It was also under development for the treatment of insomnia, drug-induced akathisia, and drug-induced dyskinesia, but development for these indications was discontinued.[3]

Interestingly, a meta-analytic review showed that pimavanserin efficacy is inferior to clozapine. However, pimavanserin has a significantly lower number of side effects for managing psychosis in  Parkinson's disease. Medicare database assessment revealed 35% lower mortality with pimavanserin compared to other atypical antipsychotics. Moreover, sensitive statistical analysis demonstrated that pimavanserin is a protective factor for the risk of falls in individuals with Parkinson's disease.[22]

References

  1. ↑ 1.0 1.1 1.2 "Nuplazid- pimavanserin tartrate capsule Nuplazid- pimavanserin tartrate tablet, coated". 21 December 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6bea44-57d6-4bac-9328-46e1ee59f83b. 
  2. ↑ 2.0 2.1 2.2 "Pimavanserin for the treatment of Parkinson's disease psychosis". Expert Opinion on Pharmacotherapy 14 (14): 1969–75. October 2013. doi:10.1517/14656566.2013.819345. PMID 24016069. 
  3. ↑ 3.0 3.1 3.2 3.3 "Pimavanserin - Acadia Pharmaceuticals - AdisInsight". http://adisinsight.springer.com/drugs/800014997. 
  4. ↑ "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. 
  5. ↑ "NUPLAZID Prescribing Information". 2018. https://www.nuplazid.com/pdf/NUPLAZID-Prescribing-Information-PI-v8-Sep-2018.pdf. 
  6. ↑ "Mechanism of action of pimavanserin in Parkinson's disease psychosis: targeting serotonin 5HT2A and 5HT2C receptors". CNS Spectrums 21 (4): 271–5. August 2016. doi:10.1017/S1092852916000407. PMID 27503570. 
  7. ↑ "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. 
  8. ↑ "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. 
  9. ↑ "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. 
  10. ↑ "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. 
  11. ↑ "Treating Parkinson's Disease - Clinical Trial Pimavanserin". Acadia Pharmaceuticals. http://www.acadia-pharm.com/programs/parkinsons.htm. 
  12. ↑ "Acadia Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial" (Press release). Acadia Pharmaceuticals. 19 March 2007. Retrieved 11 April 2009.
  13. ↑ "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=. 
  14. ↑ "FDA approves first drug to treat hallucinations and delusions associated with Parkinson's disease" (Press release). U.S. Food and Drug Administration (FDA). Retrieved 1 May 2016.
  15. ↑ "Pimavanserin (Nuplazid): A Treatment for Hallucinations and Delusions Associated With Parkinson's Disease". P & T 42 (6): 368–371. June 2017. PMID 28579723. 
  16. ↑ "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/. 
  17. ↑ "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.
  18. ↑ "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. 
  19. ↑ "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. 
  20. ↑ "FDA re-examines safety of controversial new drug". CNN. https://www.cnn.com/2018/04/25/health/fda-nuplazid-safety-evaluation-invs/index.html. 
  21. ↑ "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. 
  22. ↑ "Pimavanserin and Parkinson's Disease Psychosis: A Narrative Review". Brain Sciences 12 (10): 1286. September 2022. doi:10.3390/brainsci12101286. PMID 36291220. 



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