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Pharmacodynamics and pharmacokinetics of the novel PAR-1 antagonist vorapaxar (formerly SCH 530348) in healthy subjects

  • Pharmacodynamics
  • Published:
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Abstract

Purpose

The aim of our study was to evaluate the pharmacology of vorapaxar (SCH 530348), an oral PAR-1 antagonist, in healthy volunteers.

Methods and results

In two randomized, placebo-controlled studies, subjects received either single ascending doses of vorapaxar (0.25, 1, 5, 10, 20, or 40 mg; n = 50), multiple ascending doses of vorapaxar (1, 3, or 5 mg/day for 28 days; n = 36), a loading dose (10 or 20 mg) followed by daily maintenance doses (1 mg) for 6 days (n = 12), or placebo. Single 20- and 40-mg doses of vorapaxar completely inhibited thrombin receptor activating peptide (TRAP)-induced platelet aggregation (>80% inhibition) at 1 h and sustained this level of inhibition for ≥72 h. Multiple doses yielded complete inhibition on Day 1 (5 mg/day) and Day 7 (1 and 3 mg/day). Adverse events were generally mild, transient, and unrelated to dose.

Conclusion

Vorapaxar provided rapid and sustained dose-related inhibition of platelet aggregation without affecting bleeding or clotting times.

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Acknowledgments

The authors thank Joshua Barbach and Sean Gregory for assisting with the electronic submission of the manuscript and for providing editorial support. This assistance was funded by Schering-Plough Corporation (now Merck, Whitehouse Station, NJ, USA). The authors also wish to thank Alan Meehan of Merck for editorial support.

Conflict of interest

T Kosoglou, L Reyderman, RR Fales, R Keller, B Yang, and DL Cutler all declare that they are/were full-time employees of Schering-Plough Corporation (now Merck) at the time of the study. RG Tiessen and AA van Vliet are full-time employees of PRA International, and funding was provided to PRA International from Schering-Plough Corporation (now Merck) to conduct each study.

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Correspondence to Teddy Kosoglou.

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Kosoglou, T., Reyderman, L., Tiessen, R.G. et al. Pharmacodynamics and pharmacokinetics of the novel PAR-1 antagonist vorapaxar (formerly SCH 530348) in healthy subjects. Eur J Clin Pharmacol 68, 249–258 (2012). https://doi.org/10.1007/s00228-011-1120-6

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  • DOI: https://doi.org/10.1007/s00228-011-1120-6

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