title: A thorough QTc study of 3 doses of iloperidone including metabolic inhibition via CYP2D6 and/or CYP3A4 and a comparison to quetiapine and ziprasidone.
abstract: 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.
authors.affiliation: Department of Psychiatry and Human Behavior, University of California, Irvine - Irvine, CA 92697-3960, USA. sgpotkin@uci.edu
authors.forename: Steven G
authors.initials: SG
authors.lastname: Potkin
authors.forename: Sheldon
authors.initials: S
authors.lastname: Preskorn
authors.forename: Marla
authors.initials: M
authors.lastname: Hochfeld
authors.forename: Xiangyi
authors.initials: X
authors.lastname: Meng
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D003987:Dibenzothiazepines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004347:Drug Interactions; D016903:Drug Monitoring; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D007654:Ketoconazole / Q000494:pharmacology; D016014:Linear Models; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D017374:Paroxetine / Q000494:pharmacology; D010597:Pharmacogenetics; D010641:Phenotype; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D000069348:Quetiapine Fumarate; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D014481:United States; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D003987:Dibenzothiazepines; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D010879:Piperazines; D010880:Piperidines; D013844:Thiazoles; D000069348:Quetiapine Fumarate; D017374:Paroxetine; C092292:ziprasidone; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; C081732:iloperidone