Pimavanserin: Difference between revisions

{{Short description|Atypical antipsychotic medication}}

{{Use dmy dates|date=March 2023}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 448227829

| image = Pimavanserin structure.svg

| width = 250

<!-- Clinical data -->

| tradename = Nuplazid

| DailyMedID = Pimavanserin

| pregnancy_category =

| routes_of_administration = [[Oral administration|By mouth]]

| class = [[Atypical antipsychotic]]

| ATC_prefix = N05

| ATC_suffix = AX17

| legal_US = Rx-only

| legal_US_comment = <ref name="Nuplazid FDA label">{{cite web | title=Nuplazid- pimavanserin tartrate capsule Nuplazid- pimavanserin tartrate tablet, coated | website=DailyMed | date=21 December 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6bea44-57d6-4bac-9328-46e1ee59f83b | access-date=12 March 2023}}</ref>

<!-- Pharmacokinetic data -->

| bioavailability =

| protein_bound = 94–97%<ref name = Rev>{{cite journal | vauthors = Friedman JH | title = Pimavanserin for the treatment of Parkinson's disease psychosis | journal = Expert Opinion on Pharmacotherapy | volume = 14 | issue = 14 | pages = 1969–75 | date = October 2013 | pmid = 24016069 | doi = 10.1517/14656566.2013.819345 | s2cid = 35649566 }}</ref>

| metabolism = [[Liver|Hepatic]] ([[CYP3A4]], [[CYP3A5]], [[CYP2J2]])<ref name="Nuplazid FDA label" />

| elimination_half-life = 54–56 hours<ref name = Rev/>

| excretion =

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_supplemental = <br />706782-28-7 ([[tartrate]])

| DrugBank_Ref = {{drugbankcite|changed|drugbank}}

| DrugBank = DB05316

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 8246736

| KEGG_Ref = {{keggcite|changed|kegg}}

| KEGG = D08969

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 2111101

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 133017

| synonyms = ACP-103; BVF-036; BVF-048

<!-- Chemical data -->

| IUPAC_name = ''N''-(4-fluorophenylmethyl)-''N''-(1-methylpiperidin-4-yl)-''N<nowiki>'</nowiki>''-(4-(2-methylpropyloxy)phenylmethyl)carbamide

| C=25 | H=34 | F=1 | N=3 | O=2

| SMILES = CC(C)COc3ccc(cc3)CNC(=O)N(C(CC2)CCN2C)Cc(cc1)ccc1F

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 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)

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = RKEWSXXUOLRFBX-UHFFFAOYSA-N

'''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]], [[psychomotor agitation|agitation]], and [[major depressive disorder]].<ref name="AdisInsight">{{Cite web|url=http://adisinsight.springer.com/drugs/800014997|title = Pimavanserin - Acadia Pharmaceuticals - AdisInsight}}</ref> Unlike other [[antipsychotic]]s, pimavanserin is not a [[dopamine receptor antagonist]].<ref>{{cite journal | vauthors = Howland RH | title = Pimavanserin: An Inverse Agonist Antipsychotic Drug | journal = Journal of Psychosocial Nursing and Mental Health Services | volume = 54 | issue = 6 | pages = 21–4 | date = June 2016 | pmid = 27245248 | doi = 10.3928/02793695-20160523-01 }}</ref>

It is approved as a [[generic medication]].<ref>{{cite web | title=First-Time Generic Drug Approvals 2024 | website=U.S. [[Food and Drug Administration]] (FDA) | date=8 March 2024 | url=https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals | access-date=9 March 2024}}</ref>

==Pharmacology==

===Pharmacodynamics===

Pimavanserin acts as an [[inverse agonist]] and [[receptor antagonist|antagonist]] at serotonin 5-HT_2A <ref>{{Cite web|url=https://www.nuplazid.com/pdf/NUPLAZID-Prescribing-Information-PI-v8-Sep-2018.pdf|title=NUPLAZID Prescribing Information|date=2018}}</ref> receptors with high binding affinity ([[Dissociation constant|K_i]]&nbsp;=&nbsp;0.087&nbsp;nM) and at serotonin 5-HT_2C receptors with lower binding affinity (K_i&nbsp;=&nbsp;0.44&nbsp;nM). Pimavanserin shows low binding to [[sigma-1 receptor|σ₁ receptors]] (K_i&nbsp;=&nbsp;120&nbsp;nM) and has no appreciable affinity (K_i&nbsp;>&nbsp;300&nbsp;nM) to serotonin 5-HT_2B, dopamine (including [[dopamine receptor D2|D₂]]), [[muscarinic acetylcholine receptor|muscarinic acetylcholine]], [[histamine receptor|histamine]], or [[adrenergic receptor]]s, or to [[calcium channel]]s.<ref name="Nuplazid FDA label" /><ref>{{cite journal | vauthors = Stahl SM | title = Mechanism of action of pimavanserin in Parkinson's disease psychosis: targeting serotonin 5HT2A and 5HT2C receptors | journal = CNS Spectrums | volume = 21 | issue = 4 | pages = 271–5 | date = August 2016 | pmid = 27503570 | doi = 10.1017/S1092852916000407 | doi-access = free }}</ref>

Pimavanserin has a unique [[mechanism of action]] relative to other antipsychotics, behaving as a selective [[inverse agonist]] of the [[serotonin]] [[5-HT2A receptor|5-HT_2A receptor]], with 40-fold selectivity for this site over the [[5-HT2C receptor|5-HT_2C receptor]] and no significant [[affinity (pharmacology)|affinity]] or [[biological activity|activity]] at the [[5-HT2B receptor|5-HT_2B receptor]] or [[dopamine receptor]]s.<ref name = Rev/>

==History==

===Development===

Pimavanserin was developed by [[Acadia Pharmaceuticals]].

Pimavanserin is expected to improve the [[efficacy|effectiveness]] and [[side effect]] profile of antipsychotics.<ref name="pmid17519387">{{cite journal | vauthors = 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 | title = ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 322 | issue = 2 | pages = 862–70 | date = August 2007 | pmid = 17519387 | doi = 10.1124/jpet.107.121715 | s2cid = 28861527 }}</ref><ref name="pmid18534670">{{cite journal | vauthors = Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD | title = A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model | journal = Pharmacology Biochemistry and Behavior | volume = 90 | issue = 4 | pages = 540–4 | date = October 2008 | pmid = 18534670 | pmc = 2806670 | doi = 10.1016/j.pbb.2008.04.010 }}</ref><ref name="pmid19040345">{{cite journal|author2-link=Bryan Roth | vauthors = Abbas A, Roth BL | title = Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders | journal = Expert Opinion on Pharmacotherapy | volume = 9 | issue = 18 | pages = 3251–9 | date = December 2008 | pmid = 19040345 | doi = 10.1517/14656560802532707 | s2cid = 71240383 | url = https://zenodo.org/record/1236273 }}</ref> 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]].<ref>{{cite journal | vauthors = Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U | title = 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 | journal = Schizophrenia Research | volume = 141 | issue = 2–3 | pages = 144–52 | date = November 2012 | pmid = 22954754 | doi = 10.1016/j.schres.2012.07.029 | doi-access = free }}</ref>

The drug met expectations for a [[Phases of clinical research#Phase III|Phase III]] [[clinical trial]] for the treatment of [[Parkinson's disease]] [[psychosis]],<ref name="urlTreating Parkinsons Disease - Clinical Trial Pimavanserin - Acadia">{{cite web|url=http://www.acadia-pharm.com/programs/parkinsons.htm |title=Treating Parkinson's Disease - Clinical Trial Pimavanserin | work = Acadia Pharmaceuticals |access-date=11 April 2009 |url-status=dead |archive-url=https://web.archive.org/web/20090225122323/http://acadia-pharm.com/programs/parkinsons.htm |archive-date=25 February 2009 }}</ref> and has completed [[Phases of clinical research#Phase II|Phase II]] trials for [[adjuvant therapy|adjunctive treatment]] of [[schizophrenia]] alongside an [[antipsychotic]] medication.<ref name="pressReleaseSchiz">{{cite press release |title=Acadia Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial |publisher=Acadia Pharmaceuticals |date=19 March 2007 |url=http://news.acadia-pharm.com/phoenix.zhtml?c=125180&p=irol-newsArticle&ID=974982&highlight |access-date=11 April 2009}}</ref>

In September 2014, the United States [[Food and Drug Administration]] (FDA) granted [[breakthrough therapy]] status to Acadia's [[New Drug Application]] for pimavanserin.<ref name="urlPress Releases - Investors - Acadia">{{cite web | url = http://news.acadia-pharm.com/phoenix.zhtml?c=125180&p=irol-newsArticle&ID=1962810&highlight= | title = ACADIA Pharmaceuticals Receives FDA Breakthrough Therapy Designation for Nuplazid (Pimavanserin) for Parkinson's Disease Psychosis | publisher = Acadia Pharmaceuticals | date = 2 September 2014 }}</ref>

====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.<ref>{{cite press release |title=FDA approves first drug to treat hallucinations and delusions associated with Parkinson's disease|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm498442.htm|publisher=U.S. [[Food and Drug Administration]] (FDA) |access-date=1 May 2016}}</ref><ref>{{cite journal | vauthors = Cruz MP | title = Pimavanserin (Nuplazid): A Treatment for Hallucinations and Delusions Associated With Parkinson's Disease | journal = P & T | volume = 42 | issue = 6 | pages = 368–371 | date = June 2017 | pmid = 28579723 | pmc = 5440097 }}</ref> 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.<ref>{{Cite news|url=https://www.newspapers.com/clip/40244145/gov_panel_backs_drug_for_parkinsons/|title=Gov't panel backs drug for Parkinson's|date=30 March 2016|work=Beaver Dam Daily Citizen|access-date=7 December 2019|agency=Associated Press|issue=24|volume=105|page=A8|via=Newspapers.com}}</ref>

In June 2018, the FDA approved new dosages of pimavanserin to treat hallucinations and delusions associated with Parkinson's disease psychosis. A 34&nbsp;mg capsule and 10&nbsp;mg tablet formulation were approved. Previously, patients were required to take two 17&nbsp;mg tablets to achieve the recommenced 34&nbsp;mg dose per day. The 10&nbsp;mg dose is indicated for patients also taking [[CYP3A4]] inhibitors (e.g., [[ketoconazole]]).<ref>{{Cite press release |url=https://www.businesswire.com/news/home/20180629005125/en/ACADIA-Pharmaceuticals-Announces-FDA-Approval-New-Dosing|title=Acadia Pharmaceuticals Announces FDA Approval of New Dosing Formulation and Strength for NUPLAZID® (Pimavanserin)|date=29 June 2018|publisher=Acadia Pharmaceuticals|via=Business Wire|access-date=19 February 2019}}</ref>

==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|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&nbsp;=&nbsp;0.17–0.73; p&nbsp;=&nbsp;0.005). Longer and larger trials are suggested.<ref>{{cite journal | vauthors = Tariot PN, Cummings JL, Soto-Martin ME, Ballard C, Erten-Lyons D, Sultzer DL, Devanand DP, Weintraub D, McEvoy B, Youakim JM, Stankovic S, Foff EP | display-authors = 6 | title = Trial of Pimavanserin in Dementia-Related Psychosis | journal = The New England Journal of Medicine | volume = 385 | issue = 4 | pages = 309–319 | date = July 2021 | pmid = 34289275 | doi = 10.1056/NEJMoa2034634 | s2cid = 236175470 | doi-access = free | hdl = 10871/124190 | hdl-access = free }}</ref>

===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".<ref>{{cite web | url = https://www.cnn.com/2018/04/09/health/parkinsons-drug-nuplazid-invs/index.html | title = FDA worried drug was risky; now reports of deaths spark concern| date = 9 April 2018|publisher=CNN|access-date=9 April 2018}}</ref> The FDA began post-market monitoring of the drug to assess the validity of these claims.<ref>{{Cite news|url=https://www.cnn.com/2018/04/25/health/fda-nuplazid-safety-evaluation-invs/index.html|title= FDA re-examines safety of controversial new drug | vauthors = Ellis B, Hicken M |work=CNN|access-date=30 July 2018}}</ref> 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".<ref>{{Cite web |url= https://www.fda.gov/Drugs/DrugSafety/ucm621160.htm |title=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|website=U.S. [[Food and Drug Administration]] (FDA)|access-date=25 September 2018}}</ref>

==Research==

Pimavanserin was studied as a therapeutic agent in [[Phases of clinical research#Phase III|phase 3]] [[clinical trial]]s for major depressive disorder and schizophrenia and [[Phases of clinical research#Phase II|phase 2]] 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.<ref name="AdisInsight" />

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.<ref>{{Cite web |title=Acadia to Stop Trials Of Antipsychotic Drug After It Fails Schizophrenia Study |url=https://www.medscape.com/s/viewarticle/acadia-stop-trials-antipsychotic-drug-after-it-fails-2024a10004m5 |access-date=2024-03-15 |website=Medscape |language=en}}</ref>

==References==

{{Reflist}}

{{Antipsychotics}}

{{Serotonin receptor modulators}}

[[Category:5-HT2A antagonists]]

[[Category:Atypical antipsychotics]]

[[Category:Fluoroarenes]]

[[Category:Phenol ethers]]

[[Category:Piperidines]]

[[Category:Ureas]]

[[Category:Inverse agonists]]

[[Category:Experimental antidepressants]]