Pimavanserin

Last updated

Pimavanserin
Pimavanserin structure.svg
Clinical data
Trade names Nuplazid
Other namesACP-103; BVF-036; BVF-048
License data
Routes of
administration 		Oral [1]
Drug class Serotonin 5-HT2A receptor antagonist; Antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 94–97% [2]
Metabolism Hepatic (CYP3A4, CYP3A5, CYP2J2) [1]
Metabolites N-Desmethyl-pimavanserin
Onset of action Tmax Tooltip Time to peak levels: 6 hours [3] [4] [5]
Elimination half-life Pimavanserin: 54–57 h [2] [6]
N-Desmethyl-pimavanserin (active): 200 h [6]
Identifiers
  • N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C25H34FN3O2
Molar mass 427.564 g·mol−1
3D model (JSmol)
  • CC(C)COc3ccc(cc3)CNC(=O)N(C(CC2)CCN2C)Cc(cc1)ccc1F
  • InChI=1S/C25H34FN3O2/c1-19(2)18-31-24-10-6-20(7-11-24)16-27-25(30)29(23-12-14-28(3)15-13-23)17-21-4-8-22(26)9-5-21/h4-11,19,23H,12-18H2,1-3H3,(H,27,30) X mark.svgN
  • Key:RKEWSXXUOLRFBX-UHFFFAOYSA-N X mark.svgN
   (verify)

Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis. [6] [7] It is taken by mouth. [6]

Contents

Side effects of pimavanserin include peripheral edema and confusion. [6] Unlike other antipsychotics, pimavanserin is not a dopamine receptor antagonist, [8] 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. [6]

Pimavanserin was first approved for medical use in 2016. [6] It was approved as a generic medication in 2024. [9]

Medical uses

Pimavanserin is used in the treatment of Parkinson's disease psychosis. [6]

Available forms

Pimavanserin is available in the form of 10 mg oral tablets and 34 mg oral capsules. [6]

Side effects

Side effects of pimavanserin include peripheral edema and confusion, among others. [6]

Pharmacology

Pharmacodynamics

Activities of pimavanserin
Target Affinity (Ki, nM)
5-HT1A ND
5-HT2A 0.087–0.5 (Ki)
1.9–50 (IC50 Tooltip half-maximal inhibitory concentration)
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: [10] [11] [6] [12]

Pimavanserin acts as a selective inverse agonist or antagonist of the serotonin 5-HT2A receptor. [2] [13] [12] [14] It is also an antagonist or inverse agonist of the serotonin 5-HT2C receptor to a lesser extent. [6]

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 Tooltip half-maximal inhibitory concentration) values have been reported to be 1.9 nM at the serotonin 5-HT2A receptor and 91 nM at the serotonin 5-HT2C receptor. [12] [13] 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. [12]

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] [15]

Pharmacokinetics

Pimavanserin is slowsly absorbed and has a time to peak levels of 6 hours. [3] [4] [5] The elimination half-life of pimavanserin is 54 to 57 hours. [2] [6] The half-life of its active metabolite N-desmethylpimavanserin is 200 hours. [6]

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. [7]

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

References

  1. 1 2 3 4 "Nuplazid- pimavanserin tartrate capsule Nuplazid- pimavanserin tartrate tablet, coated". DailyMed. 21 December 2022. Retrieved 12 March 2023.
  2. 1 2 3 4 Friedman JH (October 2013). "Pimavanserin for the treatment of Parkinson's disease psychosis". Expert Opinion on Pharmacotherapy. 14 (14): 1969–75. doi:10.1517/14656566.2013.819345. PMID   24016069. S2CID   35649566.
  3. 1 2 Monti, Jaime M.; Pandi Perumal, Seithikurippu R.; Warren Spence, D.; Torterolo, Pablo (2018). "The Involvement of 5-HT2A Receptor in the Regulation of Sleep and Wakefulness, and the Potential Therapeutic Use of Selective 5-HT2A Receptor Antagonists and Inverse Agonists for the Treatment of an Insomnia Disorder". 5-HT2A Receptors in the Central Nervous System. Cham: Springer International Publishing. p. 311–337. doi:10.1007/978-3-319-70474-6_13. ISBN   978-3-319-70472-2 . Retrieved 16 January 2026. A study has been published by Ancoli-Israel et al. [87] in which the effects of pimavanserin on sleep were characterized in healthy adult volunteers. This was a randomized, placebo-controlled, double-blind study that included 45 subjects with a mean age of 51.8 ± 6.9 years. Pimavanserin (1, 2.5, 5.0 or 20.0 mg) or placebo was administered once daily in the morning, for 13 consecutive days. The morning administration of the compound was supported by its long Tmax (6 h) and t½ (55 h).
  4. 1 2 Ancoli-Israel S, Vanover KE, Weiner DM, Davis RE, van Kammen DP (February 2011). "Pimavanserin tartrate, a 5-HT(2A) receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers". Sleep Med. 12 (2): 134–141. doi:10.1016/j.sleep.2010.10.004. PMC   3137254 . PMID   21256805. Pimavanserin was administered in the morning due to its relatively long time to peak effect (Tmax) of about 6 h and a long halflife of about 55 h [30].
  5. 1 2 Vanover KE, Robbins-Weilert D, Wilbraham DG, Mant TG, van Kammen DP, Davis RE, Weiner DM (June 2007). "Pharmacokinetics, tolerability, and safety of ACP-103 following single or multiple oral dose administration in healthy volunteers". J Clin Pharmacol. 47 (6): 704–714. doi:10.1177/0091270007299431. PMID   17473118. The half-life of ACP-103 was approximately 55 hours, with a tmax at 6 hours. [...] Mean pharmacokinetic profiles after the single dose are presented in Figure 2, and ACP-103 single-dose pharmacokinetic parameters are provided in Table II. ACP-103 was slowly absorbed, with a median tmax consistently close to 6 hours for all doses tested. [...] Similar to the previous single-dose study, ACP-103 was slowly absorbed with a median tmax of 6 hours on day 1 and day 14 for all 3 doses of ACP-103.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 "Highlights of prescribing information - NUPLAZID" (PDF). www.accessdata.fda.gov.
  7. 1 2 "Pimavanserin - Acadia Pharmaceuticals - AdisInsight".
  8. ↑ Howland RH (June 2016). "Pimavanserin: An Inverse Agonist Antipsychotic Drug". Journal of Psychosocial Nursing and Mental Health Services. 54 (6): 21–4. doi:10.3928/02793695-20160523-01. PMID   27245248.
  9. ↑ "First-Time Generic Drug Approvals 2024". U.S. Food and Drug Administration. 8 March 2024. Archived from the original on 12 June 2019. Retrieved 9 March 2024.
  10. ↑ Liu, Tiqing. "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". BindingDB. Retrieved 2 December 2024.
  11. ↑ Lobo MC, Whitehurst TS, Kaar SJ, Howes OD (January 2022). "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. doi:10.1016/j.neubiorev.2021.11.032. PMC   7616977 . PMID   34838528.
  12. 1 2 3 4 Vanover KE, Weiner DM, Makhay M, Veinbergs I, Gardell LR, Lameh J, Del Tredici AL, Piu F, Schiffer HH, Ott TR, Burstein ES, Uldam AK, Thygesen MB, Schlienger N, Andersson CM, Son TY, Harvey SC, Powell SB, Geyer MA, Tolf BR, Brann MR, Davis RE (May 2006). "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. doi:10.1124/jpet.105.097006. PMID   16469866.
  13. 1 2 Caraci F, Santagati M, Caruso G, Cannavò D, Leggio GM, Salomone S, Drago F (2020). "New antipsychotic drugs for the treatment of agitation and psychosis in Alzheimer's disease: focus on brexpiprazole and pimavanserin". F1000Res. 9: 686. doi: 10.12688/f1000research.22662.1 . PMC   7344175 . PMID   32695312.
  14. ↑ "NUPLAZID Prescribing Information" (PDF). 2018.
  15. ↑ Stahl SM (August 2016). "Mechanism of action of pimavanserin in Parkinson's disease psychosis: targeting serotonin 5HT2A and 5HT2C receptors". CNS Spectrums. 21 (4): 271–275. doi: 10.1017/S1092852916000407 . PMID   27503570.
  16. ↑ Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW (August 2007). "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. doi:10.1124/jpet.107.121715. PMID   17519387. S2CID   28861527.
  17. ↑ Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD (October 2008). "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. doi:10.1016/j.pbb.2008.04.010. PMC   2806670 . PMID   18534670.
  18. ↑ Abbas A, Roth BL (December 2008). "Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders". Expert Opinion on Pharmacotherapy. 9 (18): 3251–9. doi:10.1517/14656560802532707. PMID   19040345. S2CID   71240383.
  19. ↑ Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U (November 2012). "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. doi: 10.1016/j.schres.2012.07.029 . PMID   22954754.
  20. ↑ "Treating Parkinson's Disease - Clinical Trial Pimavanserin". Acadia Pharmaceuticals. Archived from the original on 25 February 2009. Retrieved 11 April 2009.
  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. Archived from the original on 16 September 2018. Retrieved 27 October 2014.
  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. ↑ Cruz MP (June 2017). "Pimavanserin (Nuplazid): A Treatment for Hallucinations and Delusions Associated With Parkinson's Disease". P & T. 42 (6): 368–371. PMC   5440097 . PMID   28579723.
  25. ↑ "Gov't panel backs drug for Parkinson's". Beaver Dam Daily Citizen. Vol. 105, no. 24. Associated Press. 30 March 2016. p. A8. Retrieved 7 December 2019– via Newspapers.com.
  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. ↑ Tariot PN, Cummings JL, Soto-Martin ME, Ballard C, Erten-Lyons D, Sultzer DL, et al. (July 2021). "Trial of Pimavanserin in Dementia-Related Psychosis". The New England Journal of Medicine. 385 (4): 309–319. doi: 10.1056/NEJMoa2034634 . hdl: 10871/124190 . PMID   34289275. S2CID   236175470.
  28. ↑ "FDA worried drug was risky; now reports of deaths spark concern". CNN. 9 April 2018. Retrieved 9 April 2018.
  29. ↑ Ellis B, Hicken M. "FDA re-examines safety of controversial new drug". CNN. Retrieved 30 July 2018.
  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". U.S. Food and Drug Administration (FDA). Archived from the original on 5 December 2018. Retrieved 25 September 2018.
  31. ↑ "Acadia to Stop Trials Of Antipsychotic Drug After It Fails Schizophrenia Study". Medscape. Retrieved 15 March 2024.
  32. ↑ Murrough, James (23 October 2024). "Psilocybin Mechanism of Action (MOA)". ClinicalTrials.gov. Retrieved 13 November 2024.
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