Pimavanserin

Pimavanserin (ACP-103; BVF-036), 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 researched 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]

Pimavanserin
Clinical data
Trade namesNuplazid
Other namesACP-103; BVF-048
Routes of
administration		Orally (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding94–97%[1]
MetabolismHepatic (CYP3A4, CYP3A5, CYP2J2)[2]
Elimination half-life54–56 hours[1]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC25H34FN3O2
Molar mass427.564 g·mol−1
3D model (JSmol)
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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.[2][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.[1]


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]

On September 2, 2014, the United States Food and Drug Administration granted Breakthrough Therapy status to Acadia's New Drug Application for pimavanserin.[13]

FDA Approval

On April 29, 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]

On June 29, 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]

Controversy

On April 9, 2018, CNN reported that some in the FDA were concerned that 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".[18] The FDA began post-market monitoring of the drug to assess the validity of these claims.[19] On September 20, 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".[20]

See also

References
  1. 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.
  2. "Nuplazid (pimavanserin) Tablets, for Oral Use. U.S. Full Prescribing Information" (PDF). ACADIA Pharmaceuticals Inc. Retrieved 5 Nov 2018.
  3. http://adisinsight.springer.com/drugs/800014997
  4. 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.
  5. "NUPLAZID Prescribing Information" (PDF). 2018.
  6. Stahl SM (August 2016). "Mechanism of action of pimavanserin in Parkinson's disease psychosis: targeting serotonin 5HT2A and 5HT2C receptors". CNS Spectrums. 21 (4): 271–5. doi:10.1017/S1092852916000407. PMID 27503570.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. ACADIA Pharmaceuticals. "Treating Parkinson's Disease - Clinical Trial Pimavanserin - ACADIA". Archived from the original on February 25, 2009. Retrieved 2009-04-11.
  12. "ACADIA Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial" (Press release). ACADIA Pharmaceuticals. 2007-03-19. Retrieved 2009-04-11.
  13. "ACADIA Pharmaceuticals Receives FDA Breakthrough Therapy Designation for NUPLAZID™ (Pimavanserin) for Parkinson's Disease Psychosis". Press Releases. Acadia. 2014-09-02.
  14. "Press Announcements — FDA approves first drug to treat hallucinations and delusions associated with Parkinson's disease". U.S. Food and Drug Administration. Retrieved 1 May 2016.
  15. 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.
  16. "Gov't panel backs drug for Parkinson's". Beaver Dam Daily Citizen. 105 (24). Beaver Dam, Wisconsin. Associated Press. March 30, 2016. p. A8. Retrieved 7 Dec 2019 – via Newspapers.com.
  17. "ACADIA Pharmaceuticals Announces FDA Approval of New Dosing Formulation and Strength for NUPLAZID® (Pimavanserin)". www.businesswire.com. 2018-06-29. Retrieved 2019-02-19.
  18. "FDA worried drug was risky; now reports of deaths spark concern". CNN. Retrieved 9 April 2018.
  19. Investigates, Blake Ellis and Melanie Hicken, CNN. "FDA re-examines safety of Parkinson's drug". CNN. Retrieved 2018-07-30.
  20. Research, Center for Drug Evaluation and. "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". www.fda.gov. Retrieved 2018-09-25.

Further reading
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