Iloperidone: Preclinical Profile and Early Clinical Evaluation

Corbett, Rebecca; Griffiths, Lyn R.; Shipley, James E.; Shukla, Urvashi K.; Strupczewski, Joseph T.; Szczepanik, Ann Marie; Szewczak, Mark R.; Turk, D. J.; Vargas, Hugo M.; Kongsamut, S.

doi:10.1111/j.1527-3458.1997.tb00320.x

Cited by 25 publications

(16 citation statements)

References 70 publications

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“…In a study using a daily titration schedule of daily dose increases, doses up to 24 mg were found to be well-tolerated [18]. Some of the adverse effects of iloperidone in Phase I clinical trials included dizziness (lasting as long as 7 h in some cases), orthostatic hypotension with syncope, nausea, headache, fatigue, sedation and impaired balance.…”

Section: Drug Safetymentioning

confidence: 97%

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An assessment of iloperidone for the treatment of schizophrenia

Jain

2000

Expert Opinion on Investigational Drugs

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Iloperidone (Novartis' Zomariltrade mark) is an atypical antipsychotic agent for the treatment of schizophrenia. Current trends in the treatment of schizophrenia indicate that some atypical antipsychotics are being recommended as first-line therapy. Atypical antipsychotics, in addition to being dopamine (D) receptor antagonists, are all relatively potent serotonin (5-HT) receptor antagonists and are less likely than conventional dopamine antagonists to induce movement disorders. However, all of these agents differ in their receptor profiles and clinical profiles. Iloperidone, a benzisoxazole, is a mixed 5-HT(2A)/D(2)antagonist. Iloperidone was found to be more potent than its analogues when compared with haloperidol in antagonising climbing behaviour in mice. Iloperidone is extensively metabolised and the main circulating metabolite is reduced iloperidone. In patients treated with iloperidone, a low incidence of extrapyramidal symptoms and weight gain has been shown. Data from Phase II trials demonstrated efficacy in patients at doses of 8 mg/day and tolerability was good up to 32 mg/day. Phase III prospective, double-blind, randomised trials with iloperidone are in progress under the ZEUS (Zomariltrade mark Efficacy Utility and Safety) programme involving 3300 patients. Iloperidone, with a balance of activity at the dopaminergic and serotonergic receptors, has obvious advantages over clozapine and olanzapine, both of which have a similar receptor profile as they favour serotonergic over dopamine receptors. Iloperidone is likely to reach the market in 2001 and has favourable prospects in the atypical antipsychotic market for schizophrenia, which is expanding from US$ 1.5 billion in 2000 to US$ 3 billion in 2005.

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Section: Drug Safetymentioning

confidence: 97%

“…The drug was well-absorbed after oral administration, reaching peak concentration 2 -3 h after administration of a single dose [18].…”

Section: Pharmacokineticsmentioning

confidence: 99%

An assessment of iloperidone for the treatment of schizophrenia

Jain

2000

Expert Opinion on Investigational Drugs

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“…In animal experiments, iloperidone demonstrated potent, longlasting effects in several behavioral models predictive of efficacy in the relief of positive symptoms of schizophrenia that include apomorphine-induced climbing behavior in mice and avoidance responding, specifically pole climb avoidance, in rats [51]. In the unfamiliar rat paradigm, iloperidone significantly increased social interaction behavior, which suggests the potential for efficacy against the social withdrawal commonly seen in patients with schizophrenia [51].…”

Section: Results From Animal Experiments Supporting Use In the Treatmmentioning

confidence: 97%

“…In the unfamiliar rat paradigm, iloperidone significantly increased social interaction behavior, which suggests the potential for efficacy against the social withdrawal commonly seen in patients with schizophrenia [51]. Anxiolytic effects are supported by iloperidone's disinhibition of behaviors in the elevated plus maze test.…”

Section: Results From Animal Experiments Supporting Use In the Treatmmentioning

confidence: 97%

Iloperidone: a new option for the treatment of schizophrenia

Cutler¹

2009

Expert Review of Neurotherapeutics

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Schizophrenia is a debilitating condition associated with high morbidity and mortality. While currently available atypical antipsychotic agents have significantly advanced the treatment of schizophrenia, there is still a great unmet need for new, effective and better-tolerated therapies. Iloperidone, a D(2)/5-HT(2) receptor antagonist, has been recently approved by the US FDA for the acute treatment of schizophrenia in adults. Iloperidone has been shown to be effective in the treatment of schizophrenia in four short-term (4-6 weeks) and three long-term (52 weeks) studies with over 3000 patients exposed to treatment. Results also indicated a reassuring safety profile, particularly regarding extrapyramidal symptoms, akathisia and prolactin elevation, with a modest effect on weight gain and no medically important changes in cholesterol, triglycerides and glucose. As other antipsychotics, iloperidone has been shown to prolong the QTc interval. Since none of the current therapies work for every patient, a pharmacogenetic approach was used to identify genetic markers associated with increased response to iloperidone, suggesting a personalized therapeutic option for this drug. In addition, a long-term 4-week injectable formulation is being developed that may assist with patient compliance. Key development findings for iloperidone are presented here.

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“…Iloperidone has low affinity for serotonin 5HT1A, dopamine D1 and histamine H1 receptors (Ki values 168, 216 and 437 nM, respectively) and no appreciable affinity (Ki value >1,000 nM) for cholinergic muscarinic receptors 39–41. This pharmacodynamic profile with low affinity to H1 and M1 receptors would lead to minimal sedation, cognitive impairment and mild weight gain.…”

Section: Resultsmentioning

confidence: 99%

Iloperidone in the treatment of schizophrenia: an evidence-based review of its place in therapy

Tonin¹,

Wiens²,

Fernández-Llimós³

et al. 2016

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IntroductionSchizophrenia is a chronic and debilitating mental disorder that affects the patient’s and their family’s quality of life, as well as financial costs and health care settings. Despite the variety of available antipsychotics, optimal treatment outcomes are not always achieved. Novel drugs, such as iloperidone, can provide more effective, tolerable and safer strategies.AimTo review the evidence for the clinical impact of iloperidone on the treatment of patients with schizophrenia.Evidence reviewClinical trials, observational studies and meta-analyses reached a common consensus that iloperidone is as effective as haloperidol, risperidone and ziprasidone in reducing schizophrenia symptoms. Similar amounts of adverse events and discontinuations were observed with iloperidone compared to placebo and active treatments. Common adverse events are mild and include dizziness, hypotension, dry mouth and weight gain. Iloperidone can induce extension of QTc interval, and clinicians should be aware of its contraindications. In long-term trials, iloperidone also showed promising safety and tolerability profiles. The low propensity to cause akathisia, extrapyramidal symptoms (EPS), increased prolactin levels or changes to metabolic laboratory parameters support its use in practice. Results showed that iloperidone prevents relapse in stabilized patients, with a time to relapse superior to placebo and similar to haloperidol. Patients using a prior antipsychotic (eg, risperidone and aripiprazole) can easily switch to iloperidone with no serious impact on safety or efficacy. However, the acquisition costs of iloperidone may hamper its use. Further evidence comparing iloperidone with other antipsychotics, and pharmacoeconomic studies would be welcome.Place in therapyConsidering just the clinical profile of iloperidone, it represents a promising drug for treating schizophrenia, particularly in patients who are intolerant to previous antipsychotics, as well as being suitable as first-line therapy. Cost-effectiveness comparisons are needed to justify its use in clinical practice.

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Iloperidone: Preclinical Profile and Early Clinical Evaluation

Cited by 25 publications

References 70 publications

An assessment of iloperidone for the treatment of schizophrenia

An assessment of iloperidone for the treatment of schizophrenia

Iloperidone: a new option for the treatment of schizophrenia

Iloperidone in the treatment of schizophrenia: an evidence-based review of its place in therapy

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