Iloperidone for Schizophrenia

Out of the Pipeline

Peter J. Weiden, MD, and Jeﬀ rey R. Bishop, PharmD, BCPP

loperidone is a second-generation Table 1 New treatment (atypical) antipsychotic the FDA ap- Iloperidone: Fast facts option for patients Iproved in May 2009 for treating acute who have not schizophrenia in adults (Table 1). Iloperi- Brand name: Fanapt fully responded done is not a derivative (metabolite, iso- Class: Atypical antipsychotic (serotonin/ to or cannot mer, or different formulation) of any other dopamine antagonist) tolerate other antipsychotic. Clinical® Dowden trials have shown Health Indication: Media Acute schizophrenia in adults that iloperidone is effi cacious and sug- antipsychotics Approval date: May 2009 gest that for some patients its side-effect Availability date: Late 2009 profiCopyright le may beFor more favorablepersonal than that use of only other antipsychotics. Manufacturer: Vanda Pharmaceuticals, Inc. Dosing forms: 1-, 2-, 4-, 6-, 8-, 10-, and 12-mg tablets (nonscored); titration pack of Clinical implications 2x1-mg, 2x2-mg, 2x4-mg, and 2x6-mg tablets Iloperidone’s binding profi le is similar Starting dose: 1 mg bid (2 mg total daily dose) to that of other antipsychotics with rela- Target dose: 12 to 24 mg total daily dose tively stronger affi nity for serotonin (5- HT2A) than dopamine (D2) receptors, and its effi cacy is roughly comparable How iloperidone works to that of other non-clozapine antipsy- Like other antipsychotics, iloperidone’s chotics. effi cacy presumably is based on its ability Individual patients may respond dif- to block [antagonize] dopamine D2 recep- ferently to specific antipsychotics, even tors. Its chemical structure is most similar when those agents have shown equiva- to risperidone, paliperidone, and zipra- lent efficacy in clinical trials. Therefore, sidone, but its receptor binding profi le is a key therapeutic question is the degree distinguished by a relatively lower affi n- of differential efficacy—differences in ity for serotonin receptors 5-HT1A and 5- response at an individual level—among HT2C than ziprasidone, and a relative lack iloperidone and other antipsychotics. of muscarinic and histaminic antagonist The differential efficacy among ilo- properties (Table 2). peridone and other antipsychotics is The relatively higher affi nity of iloperi- unknown. Our clinical experience and done (and its metabolite P95) for the NEα1 iloperidone’s unique structure suggest, receptor correlates with the drug’s pro- however, that this agent might be help- pensity to cause orthostatic hypotension ful for certain patients who do not fully Dr. Weiden is professor of psychiatry, department of psychiatry, respond to or are unable to tolerate other Current Psychiatry and Dr. Bishop is assistant professor, department of pharmacy 46 September 2009 antipsychotics. practice and psychiatry, University of Illinois at Chicago.

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Table 2 Relative receptor binding affinities of 3 atypical antipsychotics* Binding afﬁ nity

Receptor Risperidone Ziprasidone Iloperidone Dopamine D2 High High High Serotonin 5-HT1A Low High Low Serotonin 5-HT2A High High High Serotonin 5-HT2C Moderate High Moderate† Norepinephrine NEα1 High Moderate Moderate†† Histamine H1 Moderate Moderate Low Muscarinic M1 Negligible Negligible Negligible

*Cross-comparison of binding strengths refl ects the subjective judgment of the authors. The goal is to demonstrate differences in overall binding patterns, and these estimates should not be considered an exact cross-comparison Clinical Point †Published reports of binding affi nity of iloperidone show considerable variation for the 5HT2C site † †One metabolite of iloperidone [P95] does not have CNS activity but has potent alpha-1 antagonism and may contribute to the initial Iloperidone’s orthostatic hypotension seen in clinical trials relatively strong

during initial up-titration.1 Differences hours in extensive metabolizers) can be NEα1 antagonism in iloperidone’s receptor binding profi le almost 50% longer (>24 hours) in CYP2D6 creates some risk for compared with other antipsychotics likely poor metabolizers. initial orthostatic are responsible for its different side-effect There are no recommendations to test hypotension profi le.2,3 patients for genetic variants that result in poor metabolism from CYP2D6. Rather, clinicians simply need to be aware that Pharmacokinetics this could be the source of interindividual Iloperidone is administered twice daily differences they see in iloperidone toler- and can be taken with or without food. ability, just as it is for any other medication The bioavailability of iloperidone tablets is that is a substrate for the CYP2D6 enzyme 96%, and peak plasma concentrations are system. achieved 2 to 4 hours after ingestion. Like all antipsychotics except paliperi- Interactions. Medications that inhibit the done, iloperidone is metabolized by the CYP3A4 or CYP2D6 systems can increase liver’s cytochrome P450 (CYP) system. The iloperidone plasma level when taken con- enzyme pathways CYP3A4 and CYP2D6 currently with iloperidone, even if intrinsic transform iloperidone into 2 metabolites: liver metabolism activity is normal. Fluox- one with CNS activity (P88) and one that etine and paroxetine are potent CYP2D6 does not cross the blood-brain barrier and inhibitors. Concurrent treatment with ei- is not active in the CNS (P95) but likely has ther of these selective serotonin reuptake peripheral effects. inhibitors could increase iloperidone plasma concentration by 100% or more.4 Genetic variations in CYP2D6 activity can Similarly, cotreatment with a potent substantially alter how individual patients CYP3A4 inhibitor such as ketoconazole metabolize iloperidone. The half-life of ilo- (or drinking grapefruit juice) will decrease peridone and its active metabolites differs metabolism and increase plasma concen- depending on whether someone is a poor trations of iloperidone and its active me- metabolizer (no functional CYP2D6 activ- tabolites by about 50%. Smoking status ity), intermediate metabolizer (reduced should not infl uence iloperidone plasma CYP2D6 activity), or extensive metaboliz- concentration because this drug is not a er (“normal” CYP2D6 activity). The usual primary substrate for CYP1A2, the enzyme Current Psychiatry half-life of iloperidone (approximately 18 induced by cigarette smoking. Vol. 8, No. 9 47 continued

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Table 3 Common side eff ects: Iloperidone vs other antipsychotics*

Less likely or less severe More likely or more severe Other antipsychotic with iloperidone with iloperidone Haloperidol4,8 EPS Weight gain Akathisia Orthostasis Prolactin elevation Olanzapine Dyslipidemia Orthostasis Weight gain Sedation Quetiapine Dyslipidemia EPS Sedation Risperidone4,6 EPS None Prolactin elevation Clinical Point Akathisia Ziprasidone7 EPS Weight gain Reduce iloperidone Akathisia Orthostasis dosage by 50% for Aripiprazole Akathisia Weight gain patients who are Orthostasis *Iloperidone has been compared head-to-head with haloperidol, risperidone, and ziprasidone in clinical trials. Other suggested taking a strong antipsychotic side effect liabilities are based on indirect comparisons CYP2D6 or CYP3A4 EPS: extrapyramidal symptoms inhibitor The bottom line: reduce iloperidone dos- 16 mg/d or 20 to 24 mg/d, with pla- age by 50% for patients who are taking a cebo or risperidone, 6 to 8 mg/d. strong CYP2D6 and/or CYP3A4 inhibitor These studies totaled 1,066 patients in (see Dosing below). the iloperidone treatment arms, with target dosages for iloperidone ranging from 4 to 24 mg/d. Iloperidone was more effi ca- Eﬃ cacy cious than placebo for positive, negative, In clinical trials, iloperidone was shown and overall total symptoms on the Positive to be effi cacious in treating positive and and Negative Syndrome Scale (PANSS), al- negative symptoms and general psycho- beit 4 mg/d and 8 mg/d dosages narrowly pathology in acute episodes of schizophre- missed the .05 signifi cance level. nia. It is important to consider the effi cacy The haloperidol and risperidone active studies of iloperidone within the context of controls appeared more effective than ilo- the history of its development plan. peridone in the original analyses, but these studies were not designed for analysis of Early clinical trials. Most of iloperidone’s comparative effi cacy. The protocols for all phase II and III studies were conducted of these studies used an up-titration sched- by Novartis between 1998 and 2002. Initial ule for the iloperidone groups that took 1 phase III studies included three 6-week, week to reach steady-state levels, whereas double-blind, placebo-controlled acute tri- the haloperidol and risperidone groups als comparing a range of iloperidone doses had a briefer up-titration to target dose. with placebo and an active comparator:5,6 The interpretation of these studies is • The fi rst trial compared iloperidone, 4, complex and a detailed discussion is be- 8, or 12 mg/d, with placebo or halo- yond the scope of this article. However, peridol, 15 mg/d. a post-hoc analysis that included subjects • The second compared iloperidone, 4 to who remained in the study after 2 weeks 8 mg/d or 10 to 16 mg/d, with placebo of double-blind medication showed that and risperidone, 4 to 8 mg/d. iloperidone performed comparably to ris- Current Psychiatry 48 September 2009 • The third compared iloperidone, 12 to peridone7 and haloperidol.8

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A new phase III trial. The question re- By day 7, target dosages were reached: mained whether iloperidone was as effi ca- iloperidone, 24 mg/d, and ziprasidone, cious as other fi rst-line antipsychotics but 160 mg/d.9 had been “penalized” by its slower up- Patients receiving iloperidone showed titration schedule and clinical trial design signifi cantly greater improvement in fl aws. After acquiring the development PANSS total scores at 4 weeks vs those re- rights to iloperidone from Novartis and ceiving placebo (–12.0, iloperidone; –7.1, reviewing prior study designs and results, placebo; P < .01).9 Patients receiving zipra- Vanda Pharmaceuticals designed another sidone also achieved signifi cantly greater phase III study comparing iloperidone improvement vs those receiving placebo with placebo and ziprasidone. Its purpose (–12.3; P < .05 vs placebo). was to correct for possible design fl aws in The iloperidone and ziprasidone the previous studies. groups showed signifi cantly greater im- Ziprasidone was selected as the active provement from baseline vs placebo in control because of its established effi cacy, PANSS positive (P) and negative (N) sub- Clinical Point safety, and twice-daily dosing. In this tri- scale scores. Signifi cantly more patients Clinical trials have al, researchers attempted to match the 2 receiving iloperidone (72%) than placebo shown comparable drugs’ up-titration schedules. Twice-daily (52%) experienced improvement (≥20% re- doses were given with food as follows: duction from baseline) in PANSS-P scores eﬃ cacy among • iloperidone, 1, 2, 4, 6, 8, 10, and 12 (P = .005). iloperidone, mg (days 1 to 7, respectively) Patients receiving iloperidone had a ziprasidone, • ziprasidone, 20 mg (days 1 to 2), 40 signifi cantly greater reduction in Clinical risperidone, and mg (days 3 to 4), 60 mg (days 5 to 6), Global Impression-Severity scale score vs and 80 mg (day 7). placebo (–0.65 and –0.39, respectively; P = haloperidol

Current Psychiatry Vol. 8, No. 9 49 continued on page 00

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.007), as did patients receiving ziprasidone at the highest dosage of 12 mg bid). Safety (–0.67; P = .013). studies including administration of maxi- Iloperidone met all predefi ned protocol mal doses of iloperidone with CYP3A4 criteria for effi cacy vs placebo and had effi - and CYP2D6 inhibitors showed a mean cacy equal to the highest approved dose of QTc prolongation of 19 msec without clini- ziprasidone. These results demonstrated cally signifi cant problems, and iloperidone that iloperidone has comparable effi cacy to has not been associated with serious ar- ziprasidone and support the validity of the rhythmia.4 Iloperidone should not be pre- re-analysis of earlier studies showing com- scribed to patients with signifi cant cardiac parable effi cacy between iloperidone and problems or electrolyte disturbances, how- risperidone7 or haloperidol.8 In July 2008 ever, or those taking drugs known to have the FDA issued a not approvable letter for clinically signifi cant QTc/proarrhythmic iloperidone, requesting further clinical tri- properties, such as thioridazine, droperi- als because of concerns about the drug’s dol, pimozide, or methadone.4 Clinical Point effi cacy compared with risperidone. The Iloperidone has the same safety con- Compared with FDA approved iloperidone in May 2009 af- cerns associated with other atypical anti- risperidone, ter the manufacturer provided additional psychotics, including tardive dyskinesia data from existing trials that demonstrated and neuroleptic malignant syndrome. Like iloperidone has a comparable effi cacy to risperidone. other atypical antipsychotics, iloperidone lower liability of carries a warning of increased mortality extrapyramidal Long-term eﬃ cacy. A double-blind exten- risk in elderly patients with dementia- symptoms sion study compared patients remaining related psychosis. on blinded iloperidone (4 to 16 mg/d) or Dose-related side effects include dizzi- haloperidol (5 to 20 mg/d) after complet- ness, orthostatic hypotension, and tachy- ing a 6-week effi cacy study.10 The drugs cardia. Dizziness occurred more often at showed equivalent effi cacy in preventing higher doses (20% at 20 to 24 mg/d vs 10% relapse over 46 weeks follow-up. Because at 10 to 16 mg/d vs 7% in placebo groups). this study included no placebo group, the Presumably these side effects are related to FDA does not consider it to be an interpre- NEα1 antagonism and are the basis for the table relapse prevention study. recommended dose-titration schedule de- scribed below. Clinical trials do not seem to demonstrate a dose-response relation- Tolerability ship for acute EPS or akathisia. Clinicians might consider iloperidone when seeking to switch a patient to an antipsychotic with a potentially lower side- Dosing effect burden.6,11 Compared with risperi- The approved dosage range for iloperidone, iloperidone has a lower liability for done is 12 to 24 mg/d, given as 6 to 12 mg extrapyramidal symptoms (EPS) and does bid. Some trials suggest a dose-response not cause clinically signifi cant prolactin relationship, with 24 mg being more effec- elevation (Table 3, page 48).5,7-9 Compared tive than lower target doses.5 Reduce the with ziprasidone, iloperidone has a low- target dosage of iloperidone by one-half er EPS and akathisia liability. Somewhat when administering it concomitantly with greater weight gain was seen with iloperi- medications that are strong CYP2D6 or done when compared with ziprasidone CYP3A4 inhibitors. in a 4-week study (iloperidone, +2.8 kg; ziprasidone, +1.1 kg; placebo, +0.5 kg) but Titration schedule. Because iloperidone’s the 2 drugs’ effects on triglycerides and relatively strong NEα1 antagonism creates cholesterol were comparable.9 risk for initial orthostatic hypotension, the Iloperidone has a similar degree of QTc drug needs to be titrated to the target dose Current Psychiatry 50 September 2009 prolongation as ziprasidone (mean 9 msec over 4 to 7 days: continued on page 57

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continued from page 50

• 1 mg bid at day 1 Related Resource • 2 mg bid at day 2 • Iloperidone (Fanapt) prescribing information. • 4 mg bid at day 3 www.fanapt.com/fanapt-pi-may09.pdf. • 6 mg bid at day 4 (for a target dosage Drug Brand Names of 12 mg/d) Aripiprazole • Abilify Olanzapine • Zyprexa • 8 mg bid at day 5 Chlorpromazine • Thorazine Paliperidone • Invega Clozapine • Clozaril Paroxetine • Paxil • 10 mg bid at day 6 Droperidol • Inapsine Pimozide • Orap • 12 mg bid at day 7 (for a target dos- Fluoxetine • Prozac Quetiapine • Seroquel age of 24 mg/d). Haloperidol • Haldol Risperidone • Risperdal Iloperidone • Fanapt Thioridazine • Mellaril Monitor patients for dose adjustments Ketoconazole • Nizoral Ziprasidone • Geodon based on clinical status, concomitant use of Methadone • Dolophine, Methadose other medications (including antipsychot- Disclosures ics), and tolerability of up-titration. Dr. Weiden receives research support from the National The need to titrate iloperidone slowly Institute of Mental Health and Ortho-McNeil Janssen. He is to reach effi cacious acute antipsychotic a consultant to AstraZeneca, Bristol-Myers Squibb/Otsuka Clinical Point doses may lead to delayed effectiveness America Pharmaceutical, Eli Lilly and Company, Forest, Ortho-McNeil Janssen, Pﬁ zer Inc., Schering-Plough, Vanda, Iloperidone needs compared with antipsychotics that can be and Wyeth, and a speaker for Ortho-McNeil Janssen and to be titrated to a started at therapeutic doses. This prob- Pﬁ zer Inc. lem also may be seen with up-titration of Dr. Bishop receives research/grant support from the National target dose of 12 Institute of Mental Health, NARSAD, and Ortho-McNeil Janssen. other agents with strong NEα1 proper- to 24 mg/d over ties, including chlorpromazine, clozapine, 4 to 7 days quetiapine, and risperidone, and should be considered when treating patients who iloperidone: a pooled analysis of 6-week acute-phase pivotal trials. J Clin Psychopharmacol. 2008;28(2 suppl 1):S12-19. need rapid dose escalation. 7. Hamilton J, Wolfgang C, Feeney J, et al. Effi cacy of iloperidone is comparable to risperidone in analyses of a placebo- and risperidone-controlled clinical trial for schizophrenia (pp. References NR1-033). Presented at: American Psychiatric Association 1. Subramanian N, Kalkman HO. Receptor profi le of P88- Annual Meeting; May 16-21, 2009; San Francisco, CA. 8991 and P95-12113, metabolites of the novel antipsychotic 8. Feeney J, Wolfgang C, Polymeropoulos M, et al. The iloperidone. Prog Neuropsychopharmacol Biol Psychiatry. comparative effi cacy of iloperidone and haloperidol across 2002;26(3):553-560. four short-term controlled trials (pp. NR1-026). Presented at: 2. Kalkman HO, Feuerbach D, Lötscher E. Functional American Psychiatric Association Annual Meeting; May 16- characterization of the novel antipsychotic iloperidone at 21, 2009; San Francisco, CA. human D2, D3, alpha 2C, 5-HT6, and 5-HT1A receptors. Life 9. Cutler AJ, Kalali AH, Weiden PJ, et al. Four-week, double- Sci. 2003;73(9):1151-1159. blind, placebo- and ziprasidone-controlled trial of iloperidone 3. Kalkman HO, Subramanian N, Hoyer D. Extended in patients with acute exacerbations of schizophrenia. J Clin radioligand binding profi le of iloperidone: a broad Psychopharmacol. 2008;28(2 suppl 1):S20-28. spectrum dopamine/serotonin/norepinephrine receptor 10. Torres R, Nasrallah H, Baroldi P. Iloperidone versus antagonist for the management of psychotic disorders. haloperidol as long-term maintenance treatment for patients Neuropsychopharmacology. 2001;25(6):904-914. with schizophrenia or schizoaffective disorder (pp. NR4- 4. Fanapt [package insert]. Rockville, MD: Vanda Pharmaceuticals 093). Presented at: American Psychiatric Association Annual Inc; 2009. Meeting; May 16-21, 2009; San Francisco, CA. 5. Potkin SG, Litman RE, Torres R. Effi cacy of iloperidone in 11. Kane JM, Lauriello J, Laska E, et al. Long-term effi cacy and the treatment of schizophrenia: initial phase 3 studies. J Clin safety of iloperidone: results from 3 clinical trials for the Psychopharmacol. 2008;28(2 suppl 1):S4-S11. treatment of schizophrenia. J Clin Psychopharmacol. 2008;28(2 6. Weiden PJ, Cutler AJ, Polymeropoulos MH. Safety profi le of suppl 1):S29-S35.

Bottom Line Iloperidone, a new atypical antipsychotic, may be an eff ective option for patients with schizophrenia who have not responded to other antipsychotics. The drug’s effi cacy likely is comparable to that of other antipsychotics. Its receptor binding affi nity is associated with a side-eff ect profi le that may be more tolerable for some Current Psychiatry patients compared with other antipsychotics. Vol. 8, No. 9 57

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