| Abstract |
BACKGROUND: Nonantiarrhythmic drugs may have the potential to prolong the QT interval, leading to potentially fatal ventricular tachycardias, including torsades de pointes. OBJECTIVE: This study evaluated the potential of the newer-generation, multiple-action antiepileptic drug levetiracetam, which binds to the synaptic vesicle protein SV2A, to affect cardiac repolarization, as detected by prolongation of the QT/corrected QT (QTc) interval. METHODS: This was a single-dose, randomized, placebo- and active-controlled, 4-way crossover study in healthy subjects. Subjects were randomly allocated to 1 of 4 different administration sequences. Each sequence included 3 double-blind treatments (levetirace-tam 1000 mg, levetiracetam 5000 mg, and placebo) and 1 open-label treatment (moxifloxacin 400 mg). Triplicate electrocardiograms (ECGs) were obtained at baseline and at various time points over 24 hours after each treatment using continuous Holter monitoring. ECGs were read centrally in a blinded manner. Blood samples for the determination of plasma concentrations of levetiracetam and moxifloxacin were collected before dosing and at 0.5, 1, 1.5, 2, 4, 6, 12, and 24 hours after dosing, within 5 minutes after the ECG recordings. The QT interval was corrected for heart rate using a sex- and study-specific correction (QTc(ss)) as the primary outcome measure and Fridericia's correction (QTc(F))as a secondary outcome measure. The primary analysis was performed on the time-matched, baseline-subtracted QTc(ss) (DeltaQTc(ss)). The maximum DeltaQTc(ss) difference between each active treatment and placebo (DeltaDeltaTc(ss)) was derived from a mixed-effect analysis of variance. Clinical laboratory tests, standard 12-lead ECGs, and vital signs were monitored at regular intervals. Spontaneously reported adverse events were recorded throughout the study. RESULTS: Fifty-two healthy, nonsmoking subjects (26 men, 26 women; 37 white, 9 black, 3 Hispanic, and 3 Asian/Pacific Islander) with a mean (SD) age of 28.4 (7.5) years (range, 18-45 years) and a mean weight of 71.5 (12.6) kg (range, 49-103 kg) participated in the study. Levetiracetam did not significantly prolong the QTc(ss). The upper bound of the 1-sided 95% CI for the maximum DeltaDeltaTc(ss) was 8.0 milliseconds for levetiracetam 1000 mg and 8.1 milliseconds for levetiracetam 5000 mg, with mean estimates of 4.0 and 4.1 milliseconds, respectively; similar results were obtained for the maximum DeltaDeltaQTc(F). Moxifloxacin significantly prolonged the QTc(ss), with a lower bound of the 1-sided 95% CI for the maximum DeltaDeltaQTc(ss) of 3.7 milliseconds and a mean estimate of 7.7 milliseconds. There was no statistically significant relationship between measured DeltaQTc(ss) and the levetiracetam plasma concentration, whereas a significant linear relationship was observed between measured DeltaQTc(ss) and the moxifloxacin plasma concentration (slope estimate: 4.4 milliseconds/[microg/mL]); 95% CI, 3.2-5.7; P < 0.001). No unexpected safety concerns arose based on reported adverse events, clinical laboratory evaluations, physical examinations, vital signs, or ECG monitoring during the course of the study. CONCLUSION: This randomized, placebo- and active-controlled study in healthy adult subjects found no clinically relevant changes in the QTc interval after a single levetiracetam dose of 1000 or 5000 mg. |
