Dose selection for a direct and selective factor IXa inhibitor and its complementary reversal agent

Translating pharmacokinetic and pharmacodynamic properties of the REG1 system to clinical trial design

T. J. Povsic, Mauricio G Cohen, M. Y. Chan, S. L. Zelenkofske, W. A. Wargin, R. A. Harrington, J. H. Alexander, C. P. Rusconi, R. C. Becker

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

We performed detailed pharmacokinetic and pharmacodynamic modeling of REG1, an anticoagulation system composed of the direct factor IXa (FIXa) inhibitor pegnivacogin (RB006) and its matched active control agent anivamersen (RB007), with a focus on level of target inhibition to translate phase 1 results to phase 2 dose selection. We modeled early-phase clinical data relating weightadjusted pegnivacogin dose and plasma concentration to prolongation of the activated partial thromboplastin time (aPTT). Using an in vitro calibration curve, percent FIXa inhibition was determined and related to aPTT prolongation and pegnivacogin dose and concentration. Similar methods were applied to relate anivamersen dose and level of reversal of pegnivacogin anticoagulation. Combined early-phase data suggested that ≥0.75 mg/kg pegnivacogin was associated with >99% inhibition of FIX activity and prolongation of plasma aPTT values ≈2.5 times above baseline, leading to selection of a 1 mg/kg dose for a phase 2a elective percutaneous coronary intervention study to achieve a high intensity of anticoagulation and minimize intersubject variability. Phase 2 validated our predictions, demonstrating 1 mg/kg pegnivacogin yielded plasma concentrations ≈25 μg/ml and >99% inhibition of FIX activity. The relationship between the anivamersen to pegnivacogin dose ratio and degree of pegnivacogin reversal was also validated. Our approach decreased the need for extensive dose-response studies, reducing the duration, complexity and cost of clinical development. The 1 mg/kg pegnivacogin dose and a range of anivamersen dose ratios are being tested in the phase 2b RADAR study (NCT00932100).

Original languageEnglish
Pages (from-to)21-31
Number of pages11
JournalJournal of Thrombosis and Thrombolysis
Volume32
Issue number1
DOIs
StatePublished - Jul 1 2011

Fingerprint

Factor IXa
Pharmacokinetics
Clinical Trials
Partial Thromboplastin Time
RB 006
Percutaneous Coronary Intervention
Calibration

Keywords

  • Anivamersen
  • Dose s.election.
  • Factor IXa inhibition
  • Pegnivacogin

ASJC Scopus subject areas

  • Hematology
  • Cardiology and Cardiovascular Medicine

Cite this

Dose selection for a direct and selective factor IXa inhibitor and its complementary reversal agent : Translating pharmacokinetic and pharmacodynamic properties of the REG1 system to clinical trial design. / Povsic, T. J.; Cohen, Mauricio G; Chan, M. Y.; Zelenkofske, S. L.; Wargin, W. A.; Harrington, R. A.; Alexander, J. H.; Rusconi, C. P.; Becker, R. C.

In: Journal of Thrombosis and Thrombolysis, Vol. 32, No. 1, 01.07.2011, p. 21-31.

Research output: Contribution to journalArticle

Povsic, T. J. ; Cohen, Mauricio G ; Chan, M. Y. ; Zelenkofske, S. L. ; Wargin, W. A. ; Harrington, R. A. ; Alexander, J. H. ; Rusconi, C. P. ; Becker, R. C. / Dose selection for a direct and selective factor IXa inhibitor and its complementary reversal agent : Translating pharmacokinetic and pharmacodynamic properties of the REG1 system to clinical trial design. In: Journal of Thrombosis and Thrombolysis. 2011 ; Vol. 32, No. 1. pp. 21-31.
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