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A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor.

Publication ,  Journal Article
Chan, MY; Rusconi, CP; Alexander, JH; Tonkens, RM; Harrington, RA; Becker, RC
Published in: J Thromb Haemost
May 2008

BACKGROUND: Active and safe reversibility of anticoagulation is an unmet need in clinical care. Factor IXa, required for rapid thrombin generation on platelet surfaces, is a novel target for modulating coagulation. REG1 comprises RB006 (drug) and RB007 (antidote). RB006, a ribonucleic acid aptamer, exerts its anticoagulant effect by selectively binding FIXa. RB007, the complementary oligonucleotide antidote, binds to RB006 by Watson-Crick base pairing, neutralizing its anti-FIXa activity. OBJECTIVE: To test the multiple repeat-dose safety, intraindividual pharmacodynamic reproducibility and graded active reversibility of REG1. METHODS: We randomized 39 healthy volunteers to receive either three consecutive weight-adjusted, drug-antidote treatment cycles, or double placebo. Each treatment cycle included an intravenous bolus of 0.75 mg kg(-1) RB006, followed 60 min later by a descending dose of RB007, ranging from a 2 : 1 to 0.125 : 1 antidote/drug ratio (1.5 mg kg(-1) to 0.094 mg kg(-1) RB007). Serial clinical assessments and coagulation measurements were performed through 14 days postrandomization. RESULTS: Repeat doses of RB006 achieved highly reproducible activated partial thromboplastin time (APTT) levels with low intrasubject variability (coefficient of variation 5.5%, intraclass correlation coefficient 5.8 at 15 min postdose), while repeat doses of RB007 reversed the APTT levels dose-dependently and reproducibly. There was no major bleeding and there were no other serious adverse events. CONCLUSIONS: This is the first human study demonstrating multiple repeat-dose safety, intraindividual pharmacodynamic reproducibility and graded active reversibility of an RNA aptamer-oligonucleotide antidote pair. The results lay the foundation for studying the translation of this novel anticoagulation platform to a wide variety of clinical applications.

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Published In

J Thromb Haemost

DOI

EISSN

1538-7836

Publication Date

May 2008

Volume

6

Issue

5

Start / End Page

789 / 796

Location

England

Related Subject Headings

  • Treatment Outcome
  • Reproducibility of Results
  • Pharmacokinetics
  • Partial Thromboplastin Time
  • Oligonucleotides
  • Humans
  • Factor IXa
  • Drug-Related Side Effects and Adverse Reactions
  • Double-Blind Method
  • Cardiovascular System & Hematology
 

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Chan, M. Y., Rusconi, C. P., Alexander, J. H., Tonkens, R. M., Harrington, R. A., & Becker, R. C. (2008). A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor. J Thromb Haemost, 6(5), 789–796. https://doi.org/10.1111/j.1538-7836.2008.02932.x
Chan, M. Y., C. P. Rusconi, J. H. Alexander, R. M. Tonkens, R. A. Harrington, and R. C. Becker. “A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor.J Thromb Haemost 6, no. 5 (May 2008): 789–96. https://doi.org/10.1111/j.1538-7836.2008.02932.x.
Chan MY, Rusconi CP, Alexander JH, Tonkens RM, Harrington RA, Becker RC. A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor. J Thromb Haemost. 2008 May;6(5):789–96.
Chan, M. Y., et al. “A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor.J Thromb Haemost, vol. 6, no. 5, May 2008, pp. 789–96. Pubmed, doi:10.1111/j.1538-7836.2008.02932.x.
Chan MY, Rusconi CP, Alexander JH, Tonkens RM, Harrington RA, Becker RC. A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor. J Thromb Haemost. 2008 May;6(5):789–796.
Journal cover image

Published In

J Thromb Haemost

DOI

EISSN

1538-7836

Publication Date

May 2008

Volume

6

Issue

5

Start / End Page

789 / 796

Location

England

Related Subject Headings

  • Treatment Outcome
  • Reproducibility of Results
  • Pharmacokinetics
  • Partial Thromboplastin Time
  • Oligonucleotides
  • Humans
  • Factor IXa
  • Drug-Related Side Effects and Adverse Reactions
  • Double-Blind Method
  • Cardiovascular System & Hematology