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Impact of Electrocardiographic Data Quality on Moxifloxacin Response in Thorough QT/QTc Studies

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Abstract

Background

Thorough QT studies are typically conducted for drugs with systemic bioavailability and include a positive control, typically moxifloxacin, with a well-described QTc effect.

Objective

This study tested two hypotheses: that (i) re-measuring the QT intervals based on electrocardiogram (ECG) pattern similarity improves the moxifloxacin time profile, and (ii) that study conduct influences the ability to detect a typical moxifloxacin time profile.

Methods

ECGs from 65 studies with available moxifloxacin plasma concentrations were obtained, including four studies with an unexpected moxifloxacin response. Residual error of a concentration–QT model was evaluated before and after re-measuring the QT interval based on ECG pattern similarity. Intra-replicate heart rate differences were calculated using the original heart rate measurements and the 10-s average heart rates.

Results

Similarity re-measurements reduced the residual error of the model (before vs. after of 8.43 ± 2.00 vs. 7.55 ± 1.86 ms; p < 0.001). For both original and averaged 10-s heart rate, intra-replicate heart rate differences were significantly lower (p < 0.001) in studies with the expected response than in those with an unexpected time profile.

Discussion

The pattern similarity measurement methodology reduces the residual error of the model, which influences the time profile of the moxifloxacin response. Accuracy of study conduct, represented by intra-replicate heart rate differences, separated studies with and without the expected moxifloxacin time profile.

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Acknowledgments

The opinions presented here are those of the authors and no official support or endorsement by US Food and Drug Administration is intended or should be inferred. Lars Johannesen, Christine Garnett, and Marek Malik have no conflicts of interest directly related to this article. Marek Malik is an Honorary ORISE Research Fellow of the US Food and Drug Administration.

The authors are grateful to Dr. Norman Stockbridge of the US Food and Drug Administration for his substantial guidance on the topic and his help with preparing the manuscript. This project was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration.

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Authors and Affiliations

  1. Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

    Lars Johannesen & Christine Garnett

  2. Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

    Lars Johannesen

  3. Certara, Cary, NC, USA

    Christine Garnett

  4. St. Paul’s Cardiac Electrophysiology, University of London, and Imperial College, London, UK

    Marek Malik

  5. FDA, 10903 New Hampshire Avenue Bldg 62, RM 2127E, Silver Spring, MD, 20993, USA

    Lars Johannesen

Authors
  1. Lars Johannesen
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  2. Christine Garnett
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  3. Marek Malik
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Corresponding author

Correspondence to Lars Johannesen.

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Johannesen, L., Garnett, C. & Malik, M. Impact of Electrocardiographic Data Quality on Moxifloxacin Response in Thorough QT/QTc Studies. Drug Saf 37, 183–189 (2014). https://doi.org/10.1007/s40264-014-0142-2

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  • DOI: https://doi.org/10.1007/s40264-014-0142-2

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