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A Thorough QTc Study of 3 Doses of Iloperidone Including Metabolic Inhibition Via CYP2D6 and/or CYP3A4 and a Comparison to Quetiapine and Ziprasidone

Potkin, Steven G. MD*; Preskorn, Sheldon MD; Hochfeld, Marla MD; Meng, Xiangyi PhD

Journal of Clinical Psychopharmacology: February 2013 - Volume 33 - Issue 1 - p 3–10
doi: 10.1097/JCP.0b013e31827c0314
Original Contributions

The potential for iloperidone, a D2/5-HT2A antipsychotic, to affect the heart rate–corrected QT interval (QTc) was assessed in the absence and presence of metabolic inhibitors in a randomized, open-label, multicenter study. QT interval prolongation by medications, including both conventional and atypical antipsychotic drugs, can predispose patients to cardiac arrhythmias and result in sudden death. Adults with schizophrenia or schizoaffective disorder and normal electrocardiograms at baseline (N = 188) were randomized 1:1:1:1:1 to iloperidone, 8 mg twice daily (BID), 12 mg BID, 24 mg once daily (QD); quetiapine, 375 mg BID; or ziprasidone, 80 mg BID during period 1 (no metabolic inhibitors present). Iloperidone BID produced mean changes in QTc Fridericia correction (QTcF) interval (8.5–9.0 milliseconds [ms]) similar to those produced by ziprasidone (9.6 ms) and higher than those produced by quetiapine (1.3 ms). Iloperidone, 24 mg QD, produced a mean QTcF change of 15.4 ms. Coadministration of metabolic inhibitors with iloperidone during periods 2 (paroxetine) and 3 (paroxetine and ketoconazole) resulted in greater increases in the QTc interval. Increased QTc was observed in individuals with specific cytochrome P450 2D6 polymorphisms. Up to 10% of patients on iloperidone experienced QTc intervals of 60 ms or longer in the presence of metabolic inhibition and QD dosing. However, no patients experienced QTc changes of clinical concern (QTc ≥500 ms). The most common adverse events with iloperidone were headache, anxiety, and dyspepsia. The only cardiovascular adverse events with iloperidone were non–concentration-dependent tachycardia that was mild in most patients and did not lead to further sequelae. Pharmacogenetics and recommendations are discussed.

From the *Department of Psychiatry and Human Behavior, University of California, Irvine - Irvine, CA; †Department of Psychiatry and Clinical Trials Unit, University of Kansas School of Medicine, Wichita, KS; and ‡Novartis Pharmaceuticals Corporation, East Hanover, NJ.

Received October 6, 2011; accepted after revision June 1, 2012.

Reprints: Steven G. Potkin, MD, Department of Psychiatry and Human Behavior, University of California, Irvine 5251 California Avenue, Suite 240 Irvine, CA 92697-3960 (e-mail:

This trial was sponsored by Novartis Pharmaceuticals Corporation.

Study data were presented in part at the United States Psychiatric and Mental Health Congress, November 18–21, 2010, Orlando, Florida.

© 2013 Lippincott Williams & Wilkins, Inc.