Effect of brivaracetam on cardiac repolarisation – a thorough QT study

Rosillon, Dominique; Astruc, B; Hulhoven, R.; Meeus, Marie-Anne; Troenaru, Mona-Mihaela; Watanabe, Shikiko; Stockis, Armel

doi:10.1185/03007990802278453

Cited by 33 publications

(20 citation statements)

References 27 publications

(25 reference statements)

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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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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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“…The study lacked a positive control that limits assessment of assay sensitivity; however, past clinical experience with similar monitoring techniques have consistently shown positive findings of QTc prolongation with positive controls (such as moxifloxacin), suggesting that this may not be a major deficiency (15,(17)(18)(19)(20)(21). Additionally, blood draws during placebo administration were not done, which may have led to potential unblinding of study therapy to patients.…”

Section: Discussionmentioning

confidence: 99%

A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

Münster

Rubin

Belle

et al. 2009

Clinical Cancer Research

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Purpose: This dedicated QTc phase I study, conducted in advanced-stage cancer patients, assessed the effect of a single supratherapeutic dose (800 mg) of vorinostat on the QTc interval. Experimental Design: A randomized, partially blind, placebo-controlled, two-period, crossover study was conducted. Patients (n = 25) received single doses of 800 mg vorinostat and placebo in the fasted state. Holter electrocardiogram monitoring was done before each treatment and for 24 h postdose. Blood samples for vorinostat concentration were collected through 24 h postdose following vorinostat treatment only. Prescribed electrocardiogram and blood sampling times were designed to capture the expected C max of vorinostat. Results: Twenty-four of the 25 patients enrolled in the study were included in the QTc analysis. The upper bound of the two-sided 90% confidence interval for the QTcF interval for the placebo-adjusted mean change from baseline of vorinostat was <10 ms at every time point. No patient had a QTcF change from baseline value >30 ms. One patient had QTcF values >450 ms (seen after both vorinostat and placebo administration) and none had values >480 ms. Mean AUC 0-∞ and C max values attained were on the order of ∼1.93-and ∼1.41-fold higher, respectively, compared with the 400 mg clinical dose. Based on assessment of clinical and laboratory adverse experiences, single doses of 800 mg vorinostat were generally well tolerated. Conclusions: Administration of a single supratherapeutic dose of the histone deacetylase inhibitor vorinostat is not associated with prolongation of the QTc interval. A dedicated QTc study in advanced cancer patients is a robust means for assessing risk for ventricular repolarization prolongation. (Clin Cancer Res 2009;15(22):7077-84)

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“…Drugs with short half‐lives and no active metabolites could be administered as a single dose. Drugs with a longer half‐life, like brivaracetam which has an elimination half‐life of 7–8 h, require multiple dosing (Rosillon et al. , 2008).…”

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confidence: 99%

Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development

Salvi

Karnad

Panicker

et al. 2010

British J Pharmacology

104

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Following reports of death from cardiac arrhythmias with drugs like terfenadine and cisapride, the International Conference for Harmonization formulated a guidance (E14) document. This specifies that all new drugs must undergo a 'thorough QT/QTc' (TQT) study to detect drug-induced QT prolongation, a surrogate marker of ventricular tachycardia, especially torsades de pointes (TdPs). With better understanding of data from several completed TQT studies, regulatory requirements have undergone some changes since the E14 guidance was implemented in October 2005. This article reviews the implications of the E14 guidance and the changes in its interpretation including choice of baseline QT, demonstration of assay sensitivity, statistical analysis of the effect of new drug and positive control, and PK-PD modelling. Some issues like use of automated QT measurements remain unresolved. Pharmaceutical companies too are modifying Phase 1 studies to detect QTc liability early in order to save time and resources. After the E14 guidance, development of several drugs that prolong QTc by >5 ms is being abandoned by sponsors. However, all drugs that prolong the QT interval do not increase risk of TdP. Researchers in regulatory agencies, academia and industry are working to find better biomarkers of drug-induced TdP which could prevent many useful drugs from being prematurely abandoned. Drug-induced TdP is a rare occurrence. With fewer drugs that prolong QT interval reaching the licensing stage, knowing which of these drugs are torsadogenic is proving to be elusive. Thus, paradoxically, the effectiveness of the E14 guidance itself has made prospective validation of new biomarkers difficult.

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Effect of brivaracetam on cardiac repolarisation – a thorough QT study

Abstract: The study was found to be valid in terms of assay sensitivity and the results demonstrated the absence of effects of brivaracetam on cardiac repolarisation. These results suggest that no intensive cardiac monitoring is required during the subsequent stages of brivaracetam development.

Cited by 33 publications

References 27 publications

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

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

A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development

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