Effect of single and repeated oral doses of telithromycin on cardiac QT interval in healthy subjects

Démolis, Jean-Louis; Vacheron, F; Cardus, Stéphane; Funck‐Brentano, Christian

doi:10.1067/mcp.2003.4

Cited by 44 publications

(24 citation statements)

References 16 publications

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“…Data in the FDA Briefing Package also indicate that telithromycin at 1 M increased APD 50 and APD 90 in isolated rabbit Purkinje fibers by 11 and 7%, respectively. Phase I clinical trials showed that telithromycin increased QTc by as much as 28 ms at a dose of 2400 mg, whereas other data suggest that telithromycin has no effect on the QT interval at therapeutic concentrations (800 mg) (Demolis et al, 2003). In addition to these effects of telithromycin by itself, drug-drug interaction studies with telithromycin increased plasma concentrations of cisapride, and this combination increased QTc by approximately 30 ms compared with 10 ms with either drug alone.…”

Section: Discussionmentioning

confidence: 99%

Differentiation of Arrhythmia Risk of the Antibacterials Moxifloxacin, Erythromycin, and Telithromycin Based on Analysis of Monophasic Action Potential Duration Alternans and Cardiac Instability

Wisialowski

Crimin²,

Engtrakul³

et al. 2006

J Pharmacol Exp Ther

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Antibacterial drugs are known to have varying degrees of cardiovascular liability associated with QT prolongation that can lead to the ventricular arrhythmia torsade de pointes. The purpose of these studies was to compare the assessment for the arrhythmogenic risk of moxifloxacin, erythromycin, and telithromycin. Each drug caused dose-dependent inhibition of the rapidly activating delayed rectifier potassium current encoded by the human ether-á -go-go-related gene (hERG) with IC 20 concentrations of 31 M (moxifloxacin), 21 M (erythromycin), and 11 M (telithromycin). These drugs were also evaluated in an anesthetized guinea pig model to measure changes in monophasic action potential duration (MAPD) and to quantify beat-to-beat alternations in MAPD during rapid ventricular pacing. Moxifloxacin dose dependently increased MAPD and caused a rate-dependent increase in alternans at the highest achieved free drug concentration (41 M). Erythromycin also increased MAPD at its highest free drug concentration (58 M), but alternans occurred at a relatively lower therapeutic multiple (13.9 M), and the magnitude of alternans at higher concentrations was independent of pacing rate. Further analysis of the data showed that the beat-to-beat pattern of alternans with erythromycin was less stable than that with moxifloxacin and suggestive of greater arrhythmogenic liability. In contrast to erythromycin and moxifloxacin, telithromycin decreased both MAPD and alternans at the highest achievable drug concentration (7.9 M). The relative risk at therapeutic concentrations is erythromycin Ͼ moxifloxacin Ͼ telithromycin and appears to be consistent with clinical observations of torsade de pointes in patients.

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Section: Discussionmentioning

confidence: 99%

Differentiation of Arrhythmia Risk of the Antibacterials Moxifloxacin, Erythromycin, and Telithromycin Based on Analysis of Monophasic Action Potential Duration Alternans and Cardiac Instability

Wisialowski

Crimin²,

Engtrakul³

et al. 2006

J Pharmacol Exp Ther

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“…cardiac-safety.org/) recently issued a white paper on this topic, which discussed five alternative ways for QT assessment of drugs with a heart rate effect. Methods include "Holter-bin" (Badilini and Maison-Blanche 2005;Malik 2005;Extramiana et al 2005), QTcI derived from a broad range of QT/RR pairs through continuous Holter recordings at baseline, beat-to-beat analysis (Fossa et al 2007, PK/PD modeling with heart rate as a covariate (Li 2008), and assessment of the QT interval at a fixed heart rate through, e.g., submaximal exercise (Demolis et al 1996(Demolis et al , 2000(Demolis et al , 2003. The advantages and disadvantages of the methods are discussed, but there is a lack of comparative data across methods.…”

Section: Correction Of the Qt Interval For Heart Rate Changesmentioning

confidence: 99%

Clinical ECG Assessment

Darpö

2015

Principles of Safety Pharmacology

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With the adoption of the ICH E14 guidance, the thorough QT/QTc (TQT) study has become the focus of clinical assessment of an NCE's effects on ECG parameters. The TQT study is used as a guide to the liability of a drug to cause proarrhythmias on the basis of delayed cardiac repolarization. Around 300 TQT studies have been performed since 2005 and through interactions between sponsors and regulators, especially FDA's Interdisciplinary Review Team (IRT) for QT studies. These studies can today be performed more effectively and with great confidence in the generated data. This chapter will discuss technical features and the design and analysis of TQT studies, how assay sensitivity is demonstrated, and examples from recently conducted studies. ECG assessment for drugs that cannot be safely given to healthy volunteers is also addressed, and examples from studies in cancer patients and in healthy volunteers with tyrosine kinase inhibitors are discussed. The TQT study is resource intensive and designed to solely evaluate whether an NCE prolongs the QTc interval. If data with similar confidence can be generated from other studies that are routinely performed as part of the clinical development, this would represent a more optimal use of human resources. Methods and approaches to increase the confidence in ECG data derived from "early QT assessment" in single-ascending/multiple-ascending dose studies are therefore discussed, and a path toward replacing the TQT study using these approaches will be outlined.

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“…It is widely used against Gram-positive organisms. Increasing numbers of reports of Q-T prolongation and arrhythmia associated with macrolides have encouraged researchers to investigate their electrophysiological effects (Katapadi et al 1997;Sekkarie 1997;Woywodt et al 2000;Démolis et al 2003;Kezerashvili et al 2007). Recent studies into the electrophysiological effects of 6 different macrolides on hERG currents expressed in the human embryonic kidney cell line (HEK293 cells) have shown that roxithromycin can reduce I Kr (Volberg et al 2002).…”

Section: Introductionmentioning

confidence: 98%

Blockage of hERG current and the disruption of trafficking as induced by roxithromycin

Han

Yang

Duan

et al. 2013

Can. J. Physiol. Pharmacol.

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Roxithromycin is an oral macrolide antibiotic agent that has been repeatedly reported to provoke excessive prolongation of the Q-T interval and torsades de pointes in clinical settings. To investigate the mechanisms underlying the arrhythmogenic side effects of roxithromycin, we studied the molecular mechanisms of roxithromycin on human ether-à-go-go-related gene (hERG) K(+) channels expressed in human embryonic kidney (HEK293) cells. Roxithromycin was found to inhibit wild-type (WT) hERG currents in a concentration-dependent manner with a half-maximum block concentration (IC50) of 55.8 ± 9.1 μmol/L. S6 residue hERG mutants (Y652A and F656C) showed reduced levels of hERG current blockage attributable to roxithromycin. Roxithromycin also inhibited the trafficking of hERG protein to the cell membrane, as confirmed by Western blot analysis and confocal microscopy. These findings indicate that roxithromycin may cause acquired long-QT syndrome via direct inhibition of hERG current and by disruption of hERG protein trafficking. Mutations in drug-binding sites (Y652A or F656C) of the hERG channel were found to attenuate hERG current blockage by roxithromycin, but did not significantly alter the disruption of trafficking.

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Effect of single and repeated oral doses of telithromycin on cardiac QT interval in healthy subjects

Cited by 44 publications

References 16 publications

Differentiation of Arrhythmia Risk of the Antibacterials Moxifloxacin, Erythromycin, and Telithromycin Based on Analysis of Monophasic Action Potential Duration Alternans and Cardiac Instability

Differentiation of Arrhythmia Risk of the Antibacterials Moxifloxacin, Erythromycin, and Telithromycin Based on Analysis of Monophasic Action Potential Duration Alternans and Cardiac Instability

Clinical ECG Assessment

Blockage of hERG current and the disruption of trafficking as induced by roxithromycin

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