Iloperidone: A novel atypical antipsychotic for the treatment of schizophrenia

June 1, 2008

Iloperidone, a new-generation atypical antipsychotic, is currently under investigation for the treatment of schizophrenia. In 4 separate phase 3 trials, iloperidone has demonstrated efficacy in treating schizophrenia, with total Positive and Negative Symptom Scale (PANSS) scores decreasing by a range of 8 to 14 points depending on the iloperidone dose.

Key Points

• Abstract

Iloperidone, a new-generation atypical antipsychotic, is currently under investigation for the treatment of schizophrenia. In 4 separate phase 3 trials, iloperidone has demonstrated efficacy in treating schizophrenia, with total Positive and Negative Symptom Scale (PANSS) scores decreasing by a range of 8 to 14 points depending on the iloperidone dose. The most common adverse events associated with iloperidone treatment include dizziness, dry mouth, dyspepsia, sedation, orthostatic hypotension, and weight gain. Studies have also demonstrated that, similar to ziprasidone, iloperidone is associated with a risk of corrected QT (QTc) prolongation. Currently, iloperidone does not appear to offer any unique chemical properties that separate it from the other atypical antipsychotics. The manufacturer is hoping to determine specific reliable genetic markers for predictive response to this medication. Six polymorphisms demonstrating an association with iloperidone response have been identified. However, until genotyping patients becomes cost effective, iloperidone is not likely to drastically affect current clinical practice. (Formulary. 2008;43:190–203.)

CHEMISTRY AND PHARMACOLOGY

Iloperidone is a piperidinyl-benzisoxazole derivative. Similar to other atypical antipsychotics, iloperidone demonstrates higher affinity values for 5-HT2A receptors (Ki: 5.6 nM) than for D2 receptors (Ki: 21.4 nM).8,9 This high affinity for the 5-HT2A receptor results in iloperidone's efficacy in treating the negative symptoms of schizophrenia, as well as a reduction in extrapyramidal symptoms (EPS) and anxiety. Moderate affinity for the D2 receptor results in this agent's efficacy in treating the positive symptoms of schizophrenia but also contributes to its potential to induce EPS and endocrine effects.

Other serotonin receptors that iloperidone has moderate affinity for include 5-HT1A (Ki: 93.1 nM), 5-HT2C (Ki: 42.8 nM), and 5-HT6 (Ki: 89.1 nM).8 By binding to the 5-HT1A receptor, iloperidone could potentially enhance cognition (by increasing extracellular glutamate concentrations). Affinity for the 5-HT2C receptor may enhance iloperidone's efficacy in treating the negative symptoms of schizophrenia and may also provide an anxiolytic effect. Blockade at the 5-HT6 receptor could improve cognitive function and reduce the incidence of EPS.8,10

In addition to affinities for serotonin and dopamine receptors, iloperidone has a high affinity for alpha1 receptors, moderate affinity for alpha2C receptors, and low affinity for histamine and muscarinic receptors. Blockade of alpha1 receptors may contribute to the antipsychotic activity of iloperidone but may also cause postural hypotension, dizziness, and reflex tachycardia. Blockade of alpha2C receptors may improve attention and cognitive function in patients with schizophrenia by increasing postsynaptic levels of dopamine and norepinephrine.9

PHARMACOKINETICS

Studies have demonstrated that the peak concentration (Cmax) and area under the curve (AUC) of iloperidone increase based on the dose administered. Cmax values of 2.2 ng/mL and 5.2 ng/mL have been observed with iloperidone doses of 3 and 5 mg, respectively.11 The AUC has also been observed to increase from 16 to 50 ng/mL h when the dose is increased from 3 to 5 mg.11 Studies have demonstrated a time to maximum concentration (tmax) of 2 to 4 hours in patients who were healthy, hepatically impaired, or renally impaired.12

The exact half-life (t1/2)of iloperidone is not clear because of conflicting pharmacokinetic data. According to Sainati et al,11 the t1/2 of iloperidone is 5.4 to 7.0 hours, but a more recent study reports a t1/2 of 15 hours. The t1/2 is significantly delayed to 33.7 hours in renally impaired patients versus patients without renal impairment (P=.02).11

The apparent volume of distribution of iloperidone is 2,527 L. Iloperidone demonstrates a protein binding level of 98%, which is unchanged by renal impairment (97%) or hepatic impairment (97%).12

The primary metabolic pathway for iloperidone is the reduction of the acetophenone ring structure of iloperidone to form reduced iloperidone. Cytosolic enzymes and CYP450 enzymes are most likely the primary routes by which this biotransformation occurs. The other main metabolite of iloperidone is created by the oxidation and decarboxylation of an alpha-hydroxy keto metabolite. Of note, these 2 metabolites are active and achieve higher plasma concentrations than iloperidone itself at steady-state.

Iloperidone is also metabolized to O-desmethyl iloperidone and 2-hydroxyl iloperidone through the CYP3A4 and CYP2D6 pathways, respectively. Although the concentrations of these metabolites are minimal in humans, patients with poor CYP2D6 metabolism have demonstrated a t1/2 that is increased by 88% for iloperidone and 46% for reduced iloperidone. Medications that use the CYP3A4 and 2D6 pathways may potentially be affected with the concomitant use of iloperidone.

Subsequent metabolic changes of these metabolites occur via oxidation and conjugation with glucuronic acid. Biliary excretion appears to be the predominant elimination pathway, as studies have demonstrated that the majority of the administered dose is collected in the feces.13 The manufacturer has not yet defined the percentage of renal or hepatic excretion.

CLINICAL TRIALS

Vanda analyzed data that had been collected in 3 similar 6-week trials from October 1998 to June 2002.14 Non-treatment naïve patients aged 18 to 65 years with an acute or subacute exacerbation of schizophrenia and with a Positive and Negative Symptom Scale (PANSS) total score ≥60 at screening and at baseline were enrolled in the trials. All 3 trials were randomized, double-blind, placebo- and active-controlled, parallel-group studies. Each study had a 3-day placebo run-in period, a 7-day fixed titration period, and a maintenance phase starting on Day 8 and continuing to Day 42.14

Maintenance doses used during Study 3004 (N=616) were iloperidone 4 to 8 mg/d or 10 to 16 mg/d, risperidone 4 to 8 mg/d, and placebo.14 Study 3005 randomized 686 patients to treatment with iloperidone 12 to 16 mg/d or 20 to 24 mg/d, risperidone 6 to 8 mg/d, or placebo.14 Both studies assessed change from baseline to study end on the 18-item Brief Psychiatric Rating Scale (BPRS) as the primary end point. Efficacy results were determined using the same methods as those in Study 3000 (ITT with LOCF method). BPRS scores improved significantly among patients treated with either iloperidone or risperidone in both studies. Results from these studies are summarized in Table 1.

An additional 4-week, phase 3 trial in hospitalized patients with acute psychotic exacerbation of schizophrenia evaluated the efficacy of iloperidone 24 mg/d versus placebo. The primary efficacy outcome measure was the mean change from baseline to last observation in PANSS total score. The secondary objective was to characterize the efficacy, safety, and tolerability of iloperidone 24 mg/d compared with ziprasidone and placebo. Eligible patients included those aged 18 to 65 years with a baseline PANSS total score ≥70; a Clinical Global Impression-
Severity (CGI-S) score ≥4; and a PANSS positive score ≥4 for ≥2 of the following: delusions, conceptual disorganization, hallucinations, and suspiciousness/persecution.15

Medication was titrated over a 7-day period to a maintenance dose of iloperidone 12 mg twice daily, ziprasidone 80 mg twice daily, or placebo. A total of 593 patients were randomized. Patients in the 3 groups demonstrated similar completion rates (iloperidone, 65%; ziprasidone, 66%; placebo, 60%).15 Withdrawn consent was the most frequent reason for early discontinuation, followed by unsatisfactory therapeutic effect and adverse events. A significant reduction from baseline to end point in PANSS total scores was observed with iloperidone (–12.0; P=.006) and ziprasidone (–12.3; P=.012) when compared with placebo (–7.1). Additional results can be found in Table 1.

Pharmacogenomic studies. A total of 218 iloperidone-treated patients and 105 placebo-treated patients from the Cutler et al15 study were genotyped to conduct a whole genome association study. An additional 98 patients who were treated with ziprasidone were also genotyped.16 Six single nucleotide polymorphisms (SNPs) were demonstrated to have an association with iloperidone efficacy response: rs9643483, rs875326, rs2513265, rs7837682, rs4528226, and rs11851892. The frequencies of these 6 SNPs were similar between the iloperidone and ziprasidone groups. However, the effects of these genotypes on efficacy (as assessed by PANSS total score and other subscales) were clearly different between patients treated with iloperidone and those treated with ziprasidone as compared with placebo (PANSS total: rs11851892, P=.000093 vs P=.72; rs9643483, P=.00017 vs P=.36; rs875326, P=.000021 vs P=.65; rs2513265, P=.00055 vs P=.23; rs7837682, P=.00018 vs P=.45; rs4528226, P=.00000078 vs P=.75 for iloperidone and ziprasidone, respectively). None of the 6 SNPs associated with a response to iloperidone demonstrated a significant association with a response to ziprasidone. The authors concluded that the efficacy signature of an antipsychotic appears to reflect the specificity of each drug, which may be mediated by its unique complex-binding profile, its interaction with other molecules, and its particular metabolism.17 The use of genetic markers may help clinicians optimize the risk:benefit ratio for individual patients, although additional studies are needed.16

ADVERSE EVENTS

A total of 81% of patients treated with iloperidone 4 to 8 mg/d, 78.9% of patients treated with iloperidone 10 to 16 mg/d, and 76% of patients treated with iloperidone 20 to 24 mg/d experienced ≥1 adverse event in the iloperidone/risperidone studies.14 The most frequently reported adverse events were dizziness, dry mouth, and dyspepsia. In the Cutler et al15 study, dizziness, sedation, orthostatic response, and increased weight were the most frequently reported adverse events. Adverse events resulted in discontinuation of treatment for 5% of iloperidone-treated patients compared with 8% of placebo-treated patients.15

The mean changes in corrected QT (QTc) intervals using Fridericia correction were calculated for patients during the Cutler et al15 study. The results for the mean changes in the QTc interval were similar between patients treated with iloperidone and those treated with ziprasidone at each time point (14 days: 11.4 msec and 11.3 msec for iloperidone and ziprasidone, respectively; 28 days: 7.2 msec and 6.1 msec for iloperidone and ziprasidone, respectively). Two of the iloperidone-treated and 1 of the ziprasidone-treated patients had ≥15% increases in QTc intervals. No patients with a QTc interval <500 msec at baseline experienced a change to ≥500 msec.

In previous pharmacogenomic studies, DNA polymorphisms associated with QT prolongation have been identified in several loci, including the ceramine kinase-like (CERKL) gene, which is located at 2q31.3. The CERKL protein is thought to be part of the ceramide pathway, which regulates transmembrane currents conducted by various potassium channels (including the hERG channel). DNA samples from 218 iloperidone-treated patients and 105 placebo-treated patients were genotyped for CERKL protein SNPs.15 Two SNPs within intron 2 of the CERKL gene, rs993648 and rs1441162, were significantly associated with QTc prolongation when patients were treated with iloperidone versus placebo (P<.005). On Day 14, patients heterozygous for the rs993648 SNP had a QTc interval of 4.5 msec, whereas patients homozygous for this SNP had a QTc interval of 17.8 msec ( P=2.8×10-6 ). Ziprasidone-treated patients were also genotyped for all SNPs in the CERKL gene. None of the SNPs demonstrated a correlation with QTc prolongation during ziprasidone treatment. Assessing a patient's CERKL gene could help to predict which patients may experience QTc prolongation with iloperidone treatment.18

An additional study investigated the association between variant CYP2D6 genotypes resulting in higher-than-normal drug concentrations and varying degrees of QT interval prolongation. The CYP2D6 1846G>A polymorphism, which is associated with the CYP2D6* 4 allele, includes the GG (wild-type), AA, AG, and GA genotypes. Genotype/phenotype associations were characterized using iloperidone and metabolite concentration ratios to classify patients as extensive metabolizers, intermediate metabolizers, or poor metabolizers. The analysis of the ratios demonstrated that active compound levels in plasma were greater in patients with the CYP2D6 1846G>A AA genotype. Patients treated with iloperidone whose ratio was <4 had a mean QTcF change (QT interval based on Fridericia correction) from baseline at steady-state of 10.8 msec, and those whose ratio was ≥4 had a mean change from baseline of 20.2 msec (P<.05). Patients with either non-GG or the GG genotype demonstrated adaptation with continued treatment. Iloperidone is the first atypical antipsychotic to demonstrate an association among a CYP2D6 polymorphism, plasma concentration, and QTcF interval.19

Metabolic side effects have been documented with many of the atypical antipsychotic agents. In the 2 iloperidone/risperidone studies, these adverse events were reported for patients who completed the studies. Patients treated with iloperidone 4 to 8 mg/d, 10 to 16 mg/d, or 20 to 24 mg/d gained 1.5 kg, 2.1 kg, and 1.7 kg, respectively. Risperidone-treated patients demonstrated a mean weight gain of 1.5 kg for doses of 4 to 8 mg/d.14 Changes in glucose levels were minimal during these studies, with an increase of 7.2 mg/dL observed among patients treated with iloperidone 4 to 8 mg/d, 9.0 mg/dL among patients treated with iloperidone 10 to 16 mg/d, and 16.2 mg/dL among patients treated with iloperidone 20 to 24 mg/d. Risperidone-treated patients had a mean change in blood glucose of 3.6 mg/dL. No changes were observed in total cholesterol levels among iloperidone- or risperidone-treated patients. Prolactin levels decreased after treatment with iloperidone (–38 mcg/L and –23.1 mcg/L in patients treated with iloperidone 4–8 mg/d and 10–16 mg/d, respectively). Information about prolactin levels was not collected from patients treated with iloperidone 20 to 24 mg/d.14,15

In the Cutler et al15 study, the effect of iloperidone on the Barnes Akathisia Scale (BAS) was similar to the effect of placebo at each data point and at the study's end point. Patients who were treated with ziprasidone demonstrated a worsening on the BAS from baseline, with statistically significant worsening from Day 14 through the study's end point compared with placebo (P<.05). The effect of iloperidone on the Extrapyramidal Symptoms Rating Scale (EPS-RS) was similar to the effect of placebo. Patients treated with ziprasidone demonstrated significant worsening on the EPS-RS from baseline versus placebo (P<.05).

DOSING AND ADMINISTRATION

The recommended dose of iloperidone has not yet been clearly defined by the manufacturer. In clinical trials, patients were administered doses ranging from 2 mg twice daily to 12 mg twice daily. The serum levels of iloperidone that corresponded with maximal therapeutic response were 5 to 8 ng/mL.20 Therefore, clinicians should assess iloperidone serum levels once the patient reaches steady-state to ensure optimal drug exposure. Administration of iloperidone with food does not significantly alter its absorption.11

The manufacturer is also investigating a monthly intramuscular depot formulation of iloperidone. However, information about dosing and the vehicle is not currently available.

Dr Ehret is an assistant professor, University of Connecticut, and a clinical psychiatric pharmacist, Institute of Living, Hartford, Connecticut. Dr Sopko is a psychiatric pharmacy resident, University of Connecticut and Institute of Living, Hartford. Dr Levine is a recent graduate, University of Connecticut.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, clinical manager and director of Drug Information, Department of Pharmacy Services, Hartford Hospital, Hartford, Conn, and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, assistant professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

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16. Licamele L, Volpi S, Heaton C, Mack K, et al. Pharmacogenomic study of iloperidone treatment in patients with schizophrenia identifies markers associated with efficacy [abstract]. Presented at: the 57th Annual Meeting of the American Society of Human Genetics; October 23–27, 2007; San Diego, CA. Abstract 1036/T.

17 Volpi S, Heaton C, Mack K, et al. Pharmacogenomic analysis shows differences in markers associated with response between tow atypical antipsychotics, iloperidone and ziprasidone, in the treatment of patients with schizophrenia [abstract]. Presented at: the 57th Annual Meeting of the American Society of Human Genetics; October 23–27, 2007; San Diego, CA. Abstract 1037/T.

18. Heaton C, Mack K, Volpi S, et al. Whole genome association study identifies polymorphisms in the CERKL gene associated with QT prolongation during iloperidone treatment of patients with schizophrenia [abstract]. Presented at: the 57th Annual Meeting of the American Society of Human Genetics; October 23–27, 2007; San Diego, CA. Abstract 1039/T.

19. Wolfgang CD, Polymeropoulos MH. Single-nucleotide polymorphisms in the CYP2D6 gene are correlated with iloperidone drug exposure levels, impacting the degree of QTc prolongation associated with iloperidone treatment [abstract]. Presented at: the 57th Annual Meeting of the American Society of Human Genetics; October 23–27, 2007; San Diego, CA. Abstract 1040/T.

20. Bardoli P, Wolfgang C. A pharmacokinetic (PK)-pharamcodynamic (PD) relationship exists for efficacy of iloperidone: A novel investigational atypical antipsychotic agent [abstract]. Presented at: 2007 American Psychiatric Association Annual Meeting; May 19–24, 2007; San Diego, CA. Abstract NR507.