Effect of levetiracetam on cardiac repolarization in healthy subjects: A single-dose, randomized, placebo- and active-controlled, four-way crossover study

Hulhoven, R.; Rosillon, Dominique; Bridson, William E.; Meeus, Marie-Anne; Salas, Edubijes; Stockis, Armel

doi:10.1016/j.clinthera.2008.02.002

Cited by 42 publications

(32 citation statements)

References 22 publications

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“…We have previously confirmed that moxifloxacin can consistently produce mean increases in QT (QTcF) of between 6 and 12 ms [1, 22]. In the present study, the observed prolongation in mean QTcF of 12.03 ms agrees well with the findings from other studies using moxifloxacin as a positive comparator [8, 23–29]. Indeed, the large increase observed in QTc with moxifloxacin (mean increase of ≥10 ms) may make it relatively easy to confirm the validity of the QT/QTc study, but it is likely to compromise the assay sensitivity.…”

Section: Discussionsupporting

confidence: 91%

Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers

Täubel

Naseem

Harada

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• New drugs are expected to undergo rigorous clinical electrocardiographic evaluation ('thorough QT/QTc study') during their early clinical development in order to determine any affect on cardiac repolarization. • The fluoroquinolone antibiotic moxifloxacin (400 mg) has been used as a positive comparator for thorough QT/QTc studies due to its QT prolongation (QTcF) of between 6 and 10 ms. • Positive comparators that are able to produce mean changes close to the regulatory guidelines of 5 ms, and which can be detected by the assay in use, would enable a more rigorous evaluation of the assay conditions used in evaluating new chemical entities. WHAT THIS STUDY ADDS• This thorough QT/QTc study directly compares the effects of two doses of levofloxacin and moxifloxacin on QTc in the same healthy subjects.• Mean QTc was prolonged in subjects receiving levofloxacin compared with placebo as determined by both individual and Fridericia's heart rate correction methods.• The largest time-matched differences in QTc for two doses of levofloxacin compared with placebo suggest the potential for using levofloxacin in more rigorous QT/QTc studies, providing a robust evaluation of the assay conditions used in determining potential effects on cardiac repolarization.• There is evidence to suggest that levofloxacin moderately increases heart rate in a dose-dependent fashion. AIMSTo characterize the effects of levofloxacin on QT interval in healthy subjects and the most appropriate oral positive control treatments for International Conference on Harmonization (ICH) E14 QT/QTc studies. METHODSHealthy subjects received a single dose of levofloxacin (1000 or 1500 mg), moxifloxacin (400 mg) or placebo in a four-period crossover design. Digital 12-lead ECGs were recorded in triplicate. Measurement of QT interval was performed automatically with subsequent manual onscreen over-reading using electronic callipers. Blood samples were taken for determination of levofloxacin and moxifloxacin concentrations. RESULTSMean QTcI (QT interval corrected for heart rate using a correction factor that is applicable to each individual) was prolonged in subjects receiving moxifloxacin 400 mg compared with placebo. The largest time-matched difference in QTcI for moxifloxacin compared with placebo was observed to be 13.19 ms (95% confidence interval 11.21, 15.17) at 3.5 h post dose. Prolonged mean QTcI was also observed in subjects receiving levofloxacin 1000 mg and 1500 mg compared with placebo. The largest time-matched difference in QTcI compared with placebo was observed at 3.5 h post dose for both 1000 mg and 1500 mg of levofloxacin [mean (95%) 4.42 ms (2.44, 6.39) in 1000 mg and 7.44 ms (5.47, 9.42) in 1500 mg]. A small increase in heart rate was observed with levofloxacin during the course of the study. However, moxifloxacin showed a greater increase compared with levofloxacin. CONCLUSIONSBoth levofloxacin and moxifloxacin can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a thres...

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Section: Discussionsupporting

confidence: 91%

Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers

Täubel

Naseem

Harada

et al. 2010

Brit J Clinical Pharma

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“…Although anti-epileptic drugs are generally not included in the list of drugs that cause QT prolongation 28 , recent studies using whole cell patch-recording techniques have shown that some anti-epileptic drugs (phenytoin, phenobarbital and lamotrigine) have I Kr potassium channel-blocking properties that may be clinically relevant under certain circumstances 29,30 . The present results, together with data on levetiracetam 31 , corroborate the absence of effect on cardiac repolarisation with the newer generation anti-epileptic agents: the anti-SV2A class. According to the ICH E14 guidance these results suggest that no intensive cardiac monitoring is required during the subsequent stages of brivaracetam development 7 .…”

Section: Discussionsupporting

confidence: 93%

Effect of brivaracetam on cardiac repolarisation – a thorough QT study

Rosillon

Astruc

Hulhoven

et al. 2008

Current Medical Research and Opinion

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“…We identified nine reports describing ICH E14-based TQT studies. They were TQT studies investigating levoceretizine 37, tolterodine 38, brivaracetam 39, levetiracetam 40, rivaroxaban 41, and maraviroc 42. The studies by Davis et al 43, Malhotra et al 44.…”

Section: Discussionmentioning

confidence: 99%

Highly Automated QT Measurement Techniques in 7 Thorough QT Studies Implemented under ICH E14 Guidelines

Couderc

Garnett

et al. 2011

Annals of Noninvasive Electrocardiology

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Thorough QT (TQT) studies are designed to evaluate potential effect of a novel drug on the ventricular repolarization process of the heart using QTc prolongation as a surrogate marker for torsades de pointes. The current process to measure the QT intervals from the thousands of electrocardiograms is lengthy and expensive. In this study, we propose a validation of a highlyautomatic QT interval measurement (HA-QT) method. We applied a HA-QT measurement method to the data from seven TQT studies. We investigated both the placebo and baselineadjusted QTc interval prolongation induced by moxifloxacin (positive control drug) at the time of expected peak concentration. The comparative analysis evaluated the time course of moxifloxacininduced QTc prolongation in one study as well. The absolute HA-QT data were longer than the FDA-approved QTc data. This trend was not different between ECGs from the moxifloxacin and placebo arms: 9.6±24msec on drug and 9.8±25msec on placebo. The difference between methods vanished when comparing the placebo-baseline-adjusted QTc prolongation (1.4±2.8msec, p=0.4). The differences in precision between the HA-QT and the FDA-approved measurements were not statistically different from zero: 0.1±0.1msec (p=0.7). Also, the time course of the moxifloxacininduced QTc prolongation adjusted for placebo was not statistically different between measurements methods.

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Effect of levetiracetam on cardiac repolarization in healthy subjects: A single-dose, randomized, placebo- and active-controlled, four-way crossover study

Cited by 42 publications

References 22 publications

Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers

Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers

Effect of brivaracetam on cardiac repolarisation – a thorough QT study

Highly Automated QT Measurement Techniques in 7 Thorough QT Studies Implemented under ICH E14 Guidelines

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