Pimavanserin

Pimavanserin
Clinical data
Trade names Nuplazid
Synonyms ACP-103; BVF-048
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 94–97%[1]
Metabolism Hepatic (CYP3A4, CYP3A5, CYP2J2)[2]
Elimination half-life 54–56 hours[1]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C25H34FN3O2
Molar mass 427.553 g/mol
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 under development for the treatment of schizophrenia, agitation, and major depressive disorder.[3] Unlike other antipsychotics, pimanvaserin is not a dopamine receptor antagonist, and instead acts as a highly selective antagonist of the serotonin 5-HT2A receptor.[2]

Pharmacology

Pharmacodynamics

Pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT2A 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]

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

Pimvanserin was developed by Acadia Pharmaceuticals.

Pimavanserin is expected to improve the effectiveness and side effect profile of antipsychotics.[4][5][6] 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.[7]

The drug met expectations for a Phase III clinical trial for the treatment of Parkinson's disease psychosis,[8] and has completed Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.[9]

On September 2, 2014, the United States Food and Drug Administration granted Breakthrough Therapy status to Acadia's New Drug Application for pimavanserin.[10] It was approved by the FDA to treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson's disease on April 29, 2016.[11]

In July 2018 the FDA approved a new capsule dose formulation and tablet strength of pimavanserin to treat hallucinations and delusions associated with Parkinson’s disease psychosis in a 34-mg single capsule formulation.[12]

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". [13] The FDA is currently conducting post-market monitoring of the drug to assess the validity of these claims.[14]

Society and culture

Generic names

Pimavanserin is the INN and while pimavanserin tartate is the USAN.

See also

References

  1. 1 2 3 Friedman, JH (October 2013). "Pimavanserin for the treatment of Parkinson's disease psychosis". Expert Opinion on Pharmacotherapy. 14 (14): 1969–1975. doi:10.1517/14656566.2013.819345. PMID 24016069.
  2. 1 2 3 "Nuplazid (pimavanserin) Tablets, for Oral Use. U.S. Full Prescribing Information" (PDF). ACADIA Pharmaceuticals Inc. Retrieved 1 May 2016.
  3. http://adisinsight.springer.com/drugs/800014997
  4. 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 (Aug 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.
  5. Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD (Oct 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.
  6. Abbas A, Roth BL (Dec 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.
  7. Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U (Nov 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): 144–152. doi:10.1016/j.schres.2012.07.029. PMID 22954754.
  8. ACADIA Pharmaceuticals. "Treating Parkinson's Disease - Clinical Trial Pimavanserin - ACADIA". Archived from the original on February 25, 2009. Retrieved 2009-04-11.
  9. "ACADIA Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial" (Press release). ACADIA Pharmaceuticals. 2007-03-19. Retrieved 2009-04-11.
  10. "ACADIA Pharmaceuticals Receives FDA Breakthrough Therapy Designation for NUPLAZID™ (Pimavanserin) for Parkinson's Disease Psychosis". Press Releases. Acadia. 2014-09-02.
  11. "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.
  12. "FDA approves new formulation, dosage strength of Nuplazid for Parkinson's psychosis". www.healio.com. Retrieved 2018-07-02.
  13. "FDA worried drug was risky; now reports of deaths spark concern". CNN. Retrieved 9 April 2018.
  14. Investigates, Blake Ellis and Melanie Hicken, CNN. "FDA re-examines safety of Parkinson's drug". CNN. Retrieved 2018-07-30.
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