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Preladenant, a selective adenosine A2A receptor antagonist, is not associated with QT/QTc prolongation

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Abstract

Purpose

Preladenant is an orally administered adenosine2A (A2A) receptor antagonist in phase III development for Parkinson’s disease treatment. This thorough QT/QTc study evaluated its potential effects on cardiac repolarization.

Methods

This was a randomized, double-blind, positive- and placebo-controlled, four-period crossover study performed under steady-state exposure of clinical and supratherapeutic doses of preladenant (10 mg BID and 100 mg BID, respectively, for 5 days), moxifloxacin (400 mg on day 5), or placebo in 60 healthy adult volunteers. The potential effect on QTcF was measured by the largest upper bound of 95 % one-sided CIs for the mean changes from time-matched baseline ECG recordings compared with placebo. Plasma preladenant concentrations were also determined on day 5.

Results

The QTcF difference for moxifloxacin compared with placebo exceeded 5 ms from 1 to 12 h postdose, establishing assay sensitivity. The QTcF interval was similar between the preladenant and placebo treatment groups: the upper bound of the 95 % one-sided CI for the mean difference in QTcF between preladenant and placebo was less than 10 ms at all time points for the supratherapeutic treatment group (1.3 to 5.7 ms, mean difference: −1.3 to 2.7 ms) and the therapeutic treatment group (0.4 to 4.3 ms, mean difference: −2.1 to 1.5 ms), substantially below the threshold of regulatory concern. The supratherapeutic dose (100 mg BID) provided a Cmax margin of 6.1-fold and AUC margin of 6.9-fold, respectively, compared with 10 mg BID.

Conclusions

At clinical and supratherapeutic doses, preladenant is not associated with QTc prolongation.

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Acknowledgments

Medical writing support and editorial assistance was provided by Sheena Hunt, PhD, and Susan Quiñones, PhD, of ApotheCom. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA.

Competing interests

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: ZW is an employee and stockholder of MSD, Beijing, China; FX and WHL are employees of Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA; DLC and MDT are employees and stockholders of Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA; and AT is a former employee of Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. There was no support from any other organization for the submitted work other than Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA; there were no financial relationships with any other organizations that might have had an interest in the submitted work in the previous 3 years; and there were no other relationships or activities that could appear to have influenced the submitted work.

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Authors and Affiliations

  1. Clinical Research, MSD, 20/F Park Place, 1601 Nanjing Road (West), Jing’an District, Shanghai, 200040, China

    Z. Wang

  2. Statistics, Merck Sharp & Dohme Corp, One Merck Drive, PO Box 100, Whitehouse Station, NJ, 08889-0100, USA

    F. Xuan

  3. Clinical Pharmacology, Early Stage Development, Merck Sharp & Dohme Corp, One Merck Drive, PO Box 100, Whitehouse Station, NJ, 08889-0100, USA

    W. H. Lin

  4. Clinical Pharmacology Neuroscience Lead, Merck Sharp & Dohme Corp, One Merck Drive, PO Box 100, Whitehouse Station, NJ, 08889-0100, USA

    M. D. Troyer

  5. Merck Sharp & Dohme Corp, One Merck Drive, PO Box 100, Whitehouse Station, NJ, 08889-0100, USA

    A. Tendolkar

  6. Department of Clinical Pharmacology, Merck Sharp & Dohme Corp, PO Box 1000, North Wales, PA, 19454, USA

    D. L. Cutler

Authors
  1. Z. Wang
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  2. F. Xuan
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  3. W. H. Lin
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  4. M. D. Troyer
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  5. A. Tendolkar
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  6. D. L. Cutler
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Corresponding author

Correspondence to D. L. Cutler.

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Wang, Z., Xuan, F., Lin, W.H. et al. Preladenant, a selective adenosine A2A receptor antagonist, is not associated with QT/QTc prolongation. Eur J Clin Pharmacol 69, 1761–1767 (2013). https://doi.org/10.1007/s00228-013-1541-5

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  • DOI: https://doi.org/10.1007/s00228-013-1541-5

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