Iloperidone

Iloperidone, also known as Zomaril, is an investigational atypical antipsychotic. It is being investigated mainly for the treatment of schizophrenia symptoms. 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 US FDA had accepted their NDA for iloperidone, confirming the application is ready for FDA review and approval.^[1]

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Pharmacology

Iloperidone’s IUPAC name is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone. Iloperidone is a monoamine directed towards acting upon and antagonizing specific neurotransmitters. It is considered as an ‘atypical’ antipsychotic that is less likely to cause movement disorders in patients when compared to tradition methods of psychotic treatment. Iloperidone acts on both dopamine and serotonin receptors, making it a favorable choice against competing drugs clozapine and olanzapine.^[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] Iloperidone also performed well as an antagonist in recent studies. Iloperidone was tested for both agonist and antagonist activity, and was shown to only display antagonistic properties. It was found to block the sites of noradrenaline, dopamine, and serotonin receptors. Its affinity for these particular receptors indicates that it has the potential to be a broad spectrum antipsychotic, against positive, negative, depressive and cognitive symptoms of schizophrenia.^[5]

Clinical studies

Clinical studies have shown that some patients treated with iloperidone suffer from 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. As of the year 2000, Phase III trials are currently in progress, involving 3300 patients.^[2]

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.^[6]

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.

References

1. ^ Vanda Pharmaceuticals (November 27, 2007). "Vanda Pharmaceuticals Receives FDA Acceptance of Iloperidone New Drug Application". Press release. Retrieved on 2007-11-27.
2. ^ ^{a b} Jain KK. An assessment of iloperidone for the treatment of schizophrenia. Expert Opinion On Investigational Drugs, December 2000, Pg. 2935-43.
3. ^ Barr AM, Powell SB, Markou A, Geyer MA. Iloperidone reduces sensorimotor gating deficits in pharmacological models, but not a developmental model, of disrupted prepulse inhibition in rats. Neuropharmacology, September 2006. Pg. 457-465.
4. ^ Szewczak MR, Corbett R, Rush DK, Wilmot CA, Conway PG, Strupczewski JT, Cornfeldt M. The pharmacological profile of iloperidone, a novel atypical antipsychotic agent. The Journal of Pharmacology and Experimental Therapeutics, September 1995, Pg. 1404-13.
5. ^ Hans O. Kalkman, Dominik Feuerbach, Erika Lötscher, Philippe Schoeffter. Functional characterization of the novel antipsychotic iloperidone at human D2, D3, α2C, 5-HT6, and 5-HT1A receptors. Life Sciences Vol 93, Issue 9, July 2003, Pg. 1151-1159.
6. ^ Sainati SM, Hubbard JW, Chi E, Grasing K, Brecher MB. Safety, tolerability, and effect of food on the pharmacokinetics of iloperidone (HP 873), a potential atypical antipsychotic. Journal of Clinical Pharmacology, July 1995, Pg. 713-20.