E LECTROPHYSIOLOGICAL S AFETY OF S ERTINDOLE IN D OGS WITH N ORMAL AND R EMODELED H EARTS

Inhibition of the potassium current I Kr and QT prolongation are associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of sertindole, an antipsychotic drug reported to prolong the QT interval in schizophrenic patients. In cell cultures, sertindole appeared a selective blocker of I HERG over other ion currents. For I HERG , the IC 50 was 64±7 nM, whereas I SCN5A , I Ca,L , I Ca,T , I KCNQ1/KCNE1 and I Kv4.3 were blocked in the micromolar range. In canine ventricular myocytes, the IC 50 for I Kr inhibition by sertindole was 107±21 nM. Action potentials in these cells prolonged in a reverse-rate and concentration-dependent manner at 10-300 nM sertindole. In vivo, sertindole was administered to anesthetized dogs at clinically relevant (0.05-0.20 mg/kg) and high doses (1.0-2.0 mg/kg) IV. At 0.05-0.20 mg/kg sertindole (plasma concentrations: 30-157 nM), QT c was prolonged by 1-5 % in normal dogs and by 9-20% in dogs with remodeled hearts due to chronic AV block (CAVB). TdP were not induced at these doses in normal dogs or in CAVB dogs with reproducible induction of TdP by dofetilide in previous experiments. At 1.0-2.0 mg/kg sertindole (plasma concentrations: 0.5-3.1 µM), QT c prolonged by 6-11% in normal dogs and by 22% in dofetilide-sensitive CAVB dogs. TdP occurred in 3/5 animals in the latter group. Thus, at high IV doses sertindole can pose a serious proarrhythmic risk when electrical remodeling of the ventricles is present. At clinically relevant doses, however, sertindole does not cause TdP in anesthetized dogs with normal or remodeled hearts. et al., 1998) and prolongation of action potential duration was confirmed in isolated feline (Drici et al., 1998) and rabbit hearts (Eckardt et al., 2002). Following reevaluation of the existing data, and based on new preclinical, clinical and epidemiological information, the concern about cardiac risk was outweighed by the therapeutic benefits of sertindole. This led to the reintroduction of sertindole on the European market in 2002 along with a prospective surveillance study of all patients taking the drug (Toumi, 2002). In the present study we investigated the cardiac electrophysiological effects of sertindole in vitro and in vivo to provide an ionic basis for repolarization prolongation by the drug in relation to possible proarrhythmic actions in intact dogs. The present study investigates the electrophysiological properties of sertindole from cloned cardiac ion channels to anesthetized dogs with normal and remodeled hearts. The results can be summarized as follows: 1: Sertindole is a selective blocker of I HERG over other ion currents expressed in cell cultures. 2: Sertindole causes concentration-dependent block of native I Kr and this translates into reverse-rate dependent lengthening of myocyte action potentials. 3: In anesthetized dogs, dose-dependent prolongation of in-vivo repolarization by sertindole is observed. 4: Clinically relevant doses of sertindole do not cause TdP in anesthetized normal dogs or in CAVB animals with reproducible induction of TdP by dofetilide in previous experiments. 5: High doses of sertindole induce multiple ectopic beats and TdP in the majority of these CAVB dogs. myocytes and QT prolongation in vivo. At high IV doses, sertindole can pose a serious proarrhythmic risk when electrical remodeling of the ventricles is present, as in dogs with CAVB. At clinically relevant doses, sertindole does not cause TdP in anesthetized dogs with normal or remodeled hearts.