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The effect of the REG2 Anticoagulation System on thrombin generation kinetics: a pharmacodynamic and pharmacokinetic first-in-human study.

Publication ,  Journal Article
Vavalle, JP; Rusconi, CP; Zelenkofske, S; Wargin, WA; Ortel, TL; Alexander, JH; Povsic, TJ; Becker, RC
Published in: J Thromb Thrombolysis
October 2014

The REG2 Anticoagulation System consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous active control agent, anivamersen. Its effect on thrombin generation is unknown. A prospectively designed thrombin generation study was conducted within the phase 1 ascending dose study of REG2 to assess the effect of REG2 on thrombin generation kinetics. A total of 32 healthy volunteers were recruited into four cohorts of ascending dose pegnivacogin for the phase 1 study. In this pre-specified substudy, blood samples were drawn in the presence or absence of corn trypsin inhibitor at specified times within each dosing cohort. Thrombin generation was initiated with tissue factor and thrombin generation kinetics were measured using the Calibrated Automated Thrombogram (CAT). REG2 attenuated thrombin generation in a dose-dependent manner. All parameters of the CAT assay, except for lag time, showed a dose and concentration-dependent response to pegnivacogin [time to peak thrombin generation (PTm), endogenous thrombin potential, peak thrombin generation, and velocity index (VIx)]. Reversal of the effect of pegnivacogin with anivamersen demonstrated restoration of thrombin generation without rebound effect. This first-in-human study of the effect of the REG2 Anticoagulation System on thrombin generation demonstrates concentration-dependent suppression of thrombin generation that is reversible without rebound effect, as measured by the CAT assay.

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Published In

J Thromb Thrombolysis

DOI

EISSN

1573-742X

Publication Date

October 2014

Volume

38

Issue

3

Start / End Page

275 / 284

Location

Netherlands

Related Subject Headings

  • Thrombin Time
  • Thrombin
  • Prospective Studies
  • Male
  • Humans
  • Female
  • Factor IXa
  • Double-Blind Method
  • Dose-Response Relationship, Drug
  • Cardiovascular System & Hematology
 

Citation

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Vavalle, J. P., Rusconi, C. P., Zelenkofske, S., Wargin, W. A., Ortel, T. L., Alexander, J. H., … Becker, R. C. (2014). The effect of the REG2 Anticoagulation System on thrombin generation kinetics: a pharmacodynamic and pharmacokinetic first-in-human study. J Thromb Thrombolysis, 38(3), 275–284. https://doi.org/10.1007/s11239-014-1081-6
Vavalle, J. P., C. P. Rusconi, S. Zelenkofske, W. A. Wargin, T. L. Ortel, J. H. Alexander, T. J. Povsic, and R. C. Becker. “The effect of the REG2 Anticoagulation System on thrombin generation kinetics: a pharmacodynamic and pharmacokinetic first-in-human study.J Thromb Thrombolysis 38, no. 3 (October 2014): 275–84. https://doi.org/10.1007/s11239-014-1081-6.
Vavalle JP, Rusconi CP, Zelenkofske S, Wargin WA, Ortel TL, Alexander JH, et al. The effect of the REG2 Anticoagulation System on thrombin generation kinetics: a pharmacodynamic and pharmacokinetic first-in-human study. J Thromb Thrombolysis. 2014 Oct;38(3):275–84.
Vavalle, J. P., et al. “The effect of the REG2 Anticoagulation System on thrombin generation kinetics: a pharmacodynamic and pharmacokinetic first-in-human study.J Thromb Thrombolysis, vol. 38, no. 3, Oct. 2014, pp. 275–84. Pubmed, doi:10.1007/s11239-014-1081-6.
Vavalle JP, Rusconi CP, Zelenkofske S, Wargin WA, Ortel TL, Alexander JH, Povsic TJ, Becker RC. The effect of the REG2 Anticoagulation System on thrombin generation kinetics: a pharmacodynamic and pharmacokinetic first-in-human study. J Thromb Thrombolysis. 2014 Oct;38(3):275–284.
Journal cover image

Published In

J Thromb Thrombolysis

DOI

EISSN

1573-742X

Publication Date

October 2014

Volume

38

Issue

3

Start / End Page

275 / 284

Location

Netherlands

Related Subject Headings

  • Thrombin Time
  • Thrombin
  • Prospective Studies
  • Male
  • Humans
  • Female
  • Factor IXa
  • Double-Blind Method
  • Dose-Response Relationship, Drug
  • Cardiovascular System & Hematology