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. The drug’s release is still pending, however, due to numerous setbacks.

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.

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. 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. 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.

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.

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.

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.