title: Iloperidone (Fanapt®), a novel atypical antipsychotic, is a potent HERG blocker and delays cardiac ventricular repolarization at clinically relevant concentration.
abstract: QT interval prolongation on the electrocardiogram (ECG) has extensively been reported with iloperidone, a novel antipsychotic drug. The objective of the present study was to evaluate the effects of iloperidone on cardiac ventricular repolarization at three different levels; in vitro, ex vivo and in vivo. (1) In vitro level: whole-cell patch-clamp experiments were performed on HERG-transfected HEK293 cells exposed to iloperidone 0.01-1 μmol/L (n = 35 cells, total) to assess drug effect on HERG current. (2) Ex vivo level: Langendorff retroperfusion experiments were performed on isolated hearts from male Hartley guinea pigs (n = 7) exposed to iloperidone 100 nmol/L with/without chromanol 293B 10 μmol/L to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD(90)). (3) In vivo level: ECG recordings using wireless cardiac telemetry were performed in guinea pigs (n = 5) implanted with radio transmitters and treated with a single oral gavage dose of iloperidone 3 mg/kg. (1) Patch-clamp experiments revealed an estimated IC50 for iloperidone on HERG current of 161 ± 20 nmol/L. (2) While pacing the hearts at stimulation cycle lengths of 200 or 250 ms, or during natural sinus rhythm (no external pacing), iloperidone 100 nmol/L prolonged MAPD(90) by respectively 9.2 ± 0.9, 11.2 ± 1.6 and 21.4 ± 2.3 ms. After adding chromanol 293B, MAPD(90) was further prolonged by 7.3 ± 3.3, 11.5 ± 2.3 and 29.2 ± 6.7 ms, respectively. (3) Iloperidone 3mg/kg p.o. caused a maximal 42.7 ± 10.2 ms prolongation of corrected QT interval (QTc(F)), 40 min after administration. Iloperidone prolongs the QT interval, the cardiac action potentials and is a potent HERG blocker. Patients are at increased risk of cardiac proarrhythmia during iloperidone treatment, as this drug possesses significant cardiac repolarization-delaying properties at clinically relevant concentration.
authors.affiliation: Faculté de pharmacie, Université Laval, Québec QC, Canada. patrick.vigneault@criucpq.ulaval.ca
authors.forename: Patrick
authors.initials: P
authors.lastname: Vigneault
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pilote
authors.forename: Dany
authors.initials: D
authors.lastname: Patoine
authors.forename: Chantale
authors.initials: C
authors.lastname: Simard
authors.forename: Benoit
authors.initials: B
authors.lastname: Drolet
mesh_terms: D000200:Action Potentials; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D015716:Electrocardiography, Ambulatory; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006168:Guinea Pigs; D057809:HEK293 Cells; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology / Q000633:toxicity*; D008297:Male; D018408:Patch-Clamp Techniques; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology / Q000633:toxicity*; D026902:Potassium Channel Blockers / Q000494:pharmacology / Q000633:toxicity*; D018570:Risk Assessment; D013686:Telemetry; D013997:Time Factors; D014162:Transfection
chemical_list: D014150:Antipsychotic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007555:Isoxazoles; C000606913:KCNH2 protein, human; D010880:Piperidines; D026902:Potassium Channel Blockers; C081732:iloperidone