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Iloperidone
Systematic (IUPAC) name
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone
Identifiers
CAS number 133454-47-4
ATC code none
PubChem 71360
Chemical data
Formula C 24H27FN2O4  
Mol. mass 426.481g/mol
Pharmacokinetic data
Bioavailability  ?
Protein binding ~95%
Metabolism hepatic (CYP2D6 and CYP3A4)
Half life 18-33 hours
Excretion urine and feces
Therapeutic considerations
Pregnancy cat.  ?
Legal status -only (US)
Routes Oral, injection

Iloperidone, also known as Fanapt, Fanapta, and previously known as Zomaril, is an atypical antipsychotic for the treatment of schizophrenia. It was approved by the U.S. Food and Drug Administration (FDA) for use in the United States on May 6, 2009.

Contents

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 of its display of serotonin receptor antagonism, similar to othe atypical antipsyhotics whereas the older typical antipsychotics are primarily dopamine antagonists.


Iloperidone has been shown to act as an antagonist at all tested receptors. It was found to block the sites of noradrenaline (α2C), dopamine (D2A and D3), and serotonin (5-HT1A and 5-HT6) receptors.[1] In addition, pharmacogenomic studies identified single nucleotide polymorphisms associated with an enhanced response to iloperidone during acute treatment of schizophrenia.[2]

Laboratory studies

Iloperidone performed well against a prepulse inhibition (PPI) experiment, which was designed to gauge the extent of psychotic disorders in rats. 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.[3] 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.[4]

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.[2] 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 8mg per day, and is tolerable up to 32mg per day.

Side effects

Examination of the safety and tolerability of iloperidone have shown that at a 5mg/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.[5]

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.[6] 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.[7]

Iloperidone won FDA approval for use treating schizophrenia in the United States on May 6, 2009.[8]

References

  1. ^ Hans O. Kalkman, Dominik Feuerbach, Erika Lötscher, Philippe Schoeffter (July 2003). "Functional characterization of the novel antipsychotic iloperidone at human D2, D3, α2C, 5-HT6, and 5-HT1A receptors". Life Sciences 93 (9): 1151–1159. doi:10.1016/S0024-3205(03)00419-3. PMID 12818723.  
  2. ^ a b Scott L.Iloperidone: In Schizophrenia. CNSDrugs 2009; 23(10):867-880. doi: 10.2165/10489070-000000000-00000.
  3. ^ 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.  
  4. ^ 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.  
  5. ^ 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. PMID 7560252.  
  6. ^ Vanda Pharmaceuticals (November 27, 2007). "Vanda Pharmaceuticals Receives FDA Acceptance of Iloperidone New Drug Application". Press release. http://phx.corporate-ir.net/phoenix.zhtml?c=196233&p=irol-newsArticle&ID=1081442. Retrieved 2007-11-27.  
  7. ^ Vanda Pharmaceuticals (July 28, 2008). "FDA Issues Not Approvable Letter for Iloperidone to Vanda Pharmaceuticals". Press release. http://phx.corporate-ir.net/phoenix.zhtml?c=95579&p=irol-newsArticle&ID=1179853. Retrieved 2008-08-08.  
  8. ^ Bloomberg (May 6, 2009). "Vanda’s Schizophrenia Drug Wins Approval From U.S. Regulators". Press release. http://www.bloomberg.com/apps/news?pid=20601087&sid=a4ARBmSPKWso&refer=home. Retrieved 2009-05-06.  

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