Iloperidone

Iloperidone
Clinical data
Trade names Fanapt, Zomaril
AHFS/Drugs.com Monograph
MedlinePlus a609026
License data
Routes of
administration		 Oral, injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 96% (oral; Tmax = 2–4 hours)
Protein binding ~97%
Metabolism Hepatic (CYP2D6-mediated hydroxylation and CYP3A4-mediated O-demethylation)
Elimination half-life 18–33 hours
Excretion urine (45.1–58.2%) and feces (19.9–22.1%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.106.441 Edit this at Wikidata
Chemical and physical data
Formula C24H27FN2O4
Molar mass 426.481g/mol
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Iloperidone, also known as Fanapt, Fanapta, and previously known as Zomaril, is an atypical antipsychotic for the treatment of schizophrenia.

Medical uses

Iloperidone is used for the treatment of schizophrenia. In a 2013 study in a comparison of 15 antipsychotic drugs in effectivity in treating schizophrenic symptoms, iloperidone demonstrated mild effectiveness. As effective as lurasidone, and 13 to 15% less effective than ziprasidone, chlorpromazine, and asenapine.[1]

Availability

It was approved by the U.S. Food and Drug Administration (FDA) for use in the United States on May 6, 2009.

Pharmacology

Iloperidone is a monoamine directed towards acting upon and antagonizing specific neurotransmitters, particularly multiple dopamine and serotonin receptor subtypes. It is considered an ‘atypical’ antipsychotic because it displays serotonin receptor antagonism, similar to other atypical antipsychotics. The older typical antipsychotics are primarily dopamine antagonists.

Iloperidone has been shown to act as an antagonist at all tested receptors. It exhibits high (nM) affinity to serotonin 5HT2A (Ki value of 5.6 nM), dopamine D2 (6.3 nM) and D3 (7.1 nM) and noradrenaline α1 receptors (0.36 nM)[2], moderate affinity for dopamine D4 (25 nM), serotonin 5HT6 (43 nM), 5HT7 (22 nM), and low affinity for the serotonin 5HT1A (168 nM), dopamine D1 and histamine H1 receptors. In addition, pharmacogenomic studies identified single nucleotide polymorphisms associated with an enhanced response to iloperidone during acute treatment of schizophrenia.[3][4]

Laboratory studies

Iloperidone performed well against a prepulse inhibition (PPI) experiment, which was designed to gauge the extent of sensory gating in rats, a process disrupted in schizophrenia. Prepulse inhibition is the reduction in the amount of startle the subject gives when presented with a non-startling stimulus. Those exhibiting high levels of psychosis present a deficit in PPI. Psychosis induced using PCP, apomorphine, and cirazoline, were all prevented with the concurrent administration of iloperidone. The PPI deficit normally incurred by each psychotic drug was significantly diminished by the co administration of iloperidone.[5] The results of this experiment provided strong evidence for iloperidone’s merit as an effective treatment for psychotic disorders. Iloperidone has also been shown to reduce the effects of apomorphine induced climbing behavior in mice as well as the effects of head twitching induced by 5-HT in rats.[6]

Clinical studies

Several large (n > 570 per trial), double-blind, multinational, multicentre trials showed iloperidone generally had better efficacy than placebo when using the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) scores.[3] Clinical studies have also shown that some patients treated with iloperidone show reduced extrapyramidal symptoms and weight gain. Phase II testing has shown that effectiveness in humans is possible with as low as 8 mg per day, and is tolerable up to 4 mg per day.

Side effects

Examination of the safety and tolerability of iloperidone have shown that at a 5 mg/day dose in healthy male volunteers, the drug was fairly well tolerated, although hypotension, dizziness, and somnolence were very common side effects ranging from mild to moderate in severity. A second study showed that co administration of food decreased the severity of these effects. This study also indicated that repeat administration of iloperidone could decrease the effects of hypotension.[7]

The approved dose is 12–24 mg not 5 mg. However, claims of better tolerance have been reported.

In some cases (prevalence unknown), it can greatly increase agitation and aggressivity like all antipsychotics drugs.

Dosage

Vanda Pharmaceuticals has stated that they are developing both oral and injectable formulations. The injectable formulation is being developed to be administered at four week intervals.

Regulatory approval

Hoechst Marion Roussel Inc. made initial inquiries into the drug; however, in May 1996, they discontinued research, and in June 1997 gave research rights to Titan Pharmaceuticals. Titan then handed over worldwide development, manufacturing and marketing rights to Novartis in August 1998. On June 9, 2004, Titan Pharmaceuticals announced that the Phase III development rights have been acquired by Vanda Pharmaceuticals. The original launch date was scheduled for 2002. On November 27, 2007, Vanda Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) had accepted their New Drug Application for iloperidone, confirming the application is ready for FDA review and approval.[8] On July 28, 2008, the FDA issued a not-approvable letter to Vanda Pharmaceuticals concerning the drug, stating that further trials are required before a decision can be made concerning marketed usage of iloperidone.[9]

Iloperidone was approved by the FDA for the treatment of schizophrenia in the United States on May 6, 2009.[10]

See also

References

  1. ↑ Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–62. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.
  2. ↑ Mauri MC, Paletta S, Maffini M, Colasanti A, Dragogna F, Di Pace C, Altamura AC (2014-10-13). "Clinical pharmacology of atypical antipsychotics: an update". EXCLI Journal. 13: 1163–91. PMC 4464358. PMID 26417330.
  3. 1 2 Scott L.Iloperidone: In Schizophrenia. CNSDrugs 2009; 23(10):867-880. doi:10.2165/10489070-000000000-00000.
  4. ↑ Brunton, LL (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition. New York, NY: McGraw-Hill Medical. ISBN 9780071769396.
  5. ↑ Barr AM, Powell SB, Markou A, Geyer MA (September 2006). "Iloperidone reduces sensorimotor gating deficits in pharmacological models, but not a developmental model, of disrupted prepulse inhibition in rats". Neuropharmacology. 51 (3): 457–65. doi:10.1016/j.neuropharm.2006.04.004. PMID 16762376.
  6. ↑ Szewczak MR, Corbett R, Rush DK, Wilmot CA, Conway PG, Strupczewski JT, Cornfeldt M (September 1995). "The pharmacological profile of iloperidone, a novel atypical antipsychotic agent". The Journal of Pharmacology and Experimental Therapeutics. 274 (3): 1404–13. PMID 7562515.
  7. ↑ Sainati SM, Hubbard JW, Chi E, Grasing K, Brecher MB (July 1995). "Safety, tolerability, and effect of food on the pharmacokinetics of iloperidone (HP 873), a potential atypical antipsychotic". Journal of Clinical Pharmacology. 35 (7): 713–20. doi:10.1002/j.1552-4604.1995.tb04112.x. PMID 7560252.
  8. ↑ "Vanda Pharmaceuticals Receives FDA Acceptance of Iloperidone New Drug Application" (Press release). Vanda Pharmaceuticals. November 27, 2007. Retrieved 2007-11-27.
  9. ↑ "FDA Issues Not Approvable Letter for Iloperidone to Vanda Pharmaceuticals" (Press release). Vanda Pharmaceuticals. July 28, 2008. Retrieved 2008-08-08.
  10. ↑ "Vanda's Schizophrenia Drug Wins Approval From U.S. Regulators" (Press release). Bloomberg. May 6, 2009. Retrieved 2009-05-06.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.