RESUMEN
BACKGROUND: Antipsychotic agents have been associated with a prolonged QT interval. Data on the effects of ziprasidone and haloperidol on the QTc interval are lacking. OBJECTIVE: This study aimed to characterize the effects of 2 high-dose intramuscular injections of ziprasidone and haloperidol on the QTc interval at T(max). METHODS: This randomized, single-blind study enrolled patients with schizophrenia or schizoaffective disorder in whom long-term antipsychotic therapy was indicated. Patients were randomized to receive 2 high-dose intramuscular injections of ziprasidone (20 and 30 mg) or haloperidol (7.5 and 10 mg) separated by 4 hours. The primary outcome measure was the mean change from baseline in QTc at the T(max) of each injection. Each dose administration was followed by serial ECG and blood sampling for pharmacokinetic determinations. Twelve-lead ECG data were obtained immediately before and at predetermined times after injections. ECG tracings were read by a blinded central reader. Blood samples were obtained immediately before and after injections. Point estimates and 95% CIs for mean QTc and changes from baseline in QTc were estimated. No between-group hypothesis tests were conducted. For the assessments of tolerability and safety profile, patients underwent physical examination, including measurement of vital signs, clinical laboratory evaluation, and monitoring for adverse events (AEs) using spontaneous reporting. RESULTS: A total of 59 patients were assigned to treatment, and 58 received study medication (ziprasidone, 31 patients; haloperidol, 27; age range, 21-72 years; 79% male). After the first injection, mean (95% CI) changes from baseline were 4.6 msec (0.4-8.9) with ziprasidone (n = 25) and 6.0 msec (1.4-10.5) with haloperidol (n = 24). After the second injection, these values were 12.8 msec (6.7-18.8) and 14.7 msec (10.2-19.2), respectively. Mild and transient changes in heart rate and blood pressure were observed with both treatments. None of the patients had a QTc interval >480 msec. Two patients in the ziprasidone group experienced QTc prolongation >450 msec (457 and 454 msec) and QTc changes that exceeded 60 msec (62 and 76 msec) relative to the time-matched baseline values. With haloperidol, QTc interval values were <450 msec with no changes >60 msec. Treatment-emergent AEs were reported in 29 of 31 patients (93.5%) in the ziprasidone group and 25 of 27 patients (92.6%) in the haloperidol group; most events were of mild or moderate severity. Frequently reported AEs were somnolence (90.3% and 81.5%, respectively), dizziness (22.6% and 7.4%), anxiety (16.1% and 7.4%), extrapyramidal symptoms (6.5% and 33.3%), agitation (6.5% and 18.5%), and insomnia (0% and 14.8%). CONCLUSIONS: In this study of the effects of high-dose ziprasidone and haloperidol in patients with schizophrenic disorder, none of the patients had a QTc interval >480 msec, and changes from baseline QTc interval were clinically modest with both drugs. Both drugs were generally well tolerated.
Asunto(s)
Antipsicóticos/efectos adversos , Haloperidol/efectos adversos , Piperazinas/efectos adversos , Tiazoles/efectos adversos , Adulto , Anciano , Antipsicóticos/administración & dosificación , Antipsicóticos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Electrocardiografía , Femenino , Haloperidol/administración & dosificación , Haloperidol/uso terapéutico , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Trastornos Psicóticos/tratamiento farmacológico , Esquizofrenia/tratamiento farmacológico , Método Simple Ciego , Tiazoles/administración & dosificación , Tiazoles/uso terapéutico , Adulto JovenRESUMEN
STUDY OBJECTIVE: To characterize the effect of oral ziprasidone and haloperidol on the corrected QT (QTc) interval under steady-state conditions. Design. Prospective, randomized, open-label, parallel-group study. SETTING: Inpatient clinical research facility. Patients Fifty-nine adults (age range 25-59 yrs) with schizophrenia or schizoaffective disorder who had no clinically significant abnormality on electrocardiogram (ECG) at screening. Intervention. During period 1 (days -10 to -4), antipsychotic and anticholinergic drugs were tapered. On the first day (day -3) of period 2, the drugs were discontinued, and placebo was given for the next 3 days (days -2 to 0). On the last day (day 0) of period 2, serial baseline ECGs were collected. During period 3 (days 1-16), patients received escalating oral doses of ziprasidone and haloperidol to reach steady state. Period 4 (days 17-19) allowed for study drug washout and initiation of outpatient antipsychotic therapy; safety assessments were also performed during this period. MEASUREMENTS AND RESULTS: At each steady-state dose level, three ECGs and a serum or plasma sample were collected at the predicted time of peak exposure to the administered drug. Point estimates and 95% confidence intervals (CIs) were determined for the mean QTc interval at baseline and for the mean change from baseline in QTc at each steady-state dose level. Mean changes from baseline in the QTc interval (msec) for ziprasidone were 4.5 (95% CI 1.9-7.1), 19.5 (95% CI 15.5-23.4), and 22.5 (95% CI 15.7- 29.4) for steady-state doses of 40, 160, and 320 mg/day, respectively; for haloperidol, -1.2 (95% CI -4.1-1.7), 6.6 (95% CI 1.6-11.7), and 7.2 (95% CI 1.4-13.1) for steady-state doses of 2.5, 15, and 30 mg/day. Although no patient in either treatment group experienced a QTc interval of 450 msec or greater, the QTc interval increased 30 msec or more in 11 and 17 ziprasidone-treated patients at 160 and 320 mg/day, respectively, and in 3 and 5 haloperidol-treated patients at 15 and 30 mg/day, respectively. Most treatment-emergent adverse drug reactions were mild in intensity, and none were severe. CONCLUSION: The QTc interval in ziprasidone- and haloperidol-treated patients increased with dose. Treatment with high doses of ziprasidone or haloperidol did not result in any patient experiencing a QTc interval of 450 msec or greater.