Abstract 14661: RB006 a Direct FIXa Inhibitor Provides Potent Concentration Dependent Suppression of Thrombin Generation
Introduction: As an important determinant of thrombin generation, FIXa plays a pivotal role in the development of venous thromboembolism (VTE). RB006 (IV and SC), a direct FIXa inhibitor, may offer a new therapy for VTE. The amount of FIXa inhibition required for successful VTE prevention and effective treatment is not known. To better define potential dosing of RB006 for future VTE studies, we evaluated the inhibition of thrombin generation by quartiles of RB006 concentration.
Methods: In the SC101 study, 28 healthy volunteers received single SC RB006 doses of 0.5, 1, or 3 mg/kg or placebo (excluding planned RB007 reversal). Thrombin generation as measured by Calibrated Automated Thrombography (CAT) was determined at multiple time points for each dose level. Plasma concentrations of RB006 were collected at each dose for up to 8 days after administration. Changes in CAT parameters of Lag Time (LT), Peak Time (PTm), Peak Thrombin Generation (PTG), Endogenous Thrombin Potential (ETP), and Velocity Index (VIx) were evaluated by quartile (Q) of RB006 plasma concentration.
Results: LT was generally unaffected by RB006, while PTm was modestly prolonged. In contrast, PTG, ETP and VIx were each influenced by RB006 administration, with concentration dependent degrees of thrombin inhibition. Changes in ETP, PTG and VIx were observed with RB006 concentrations, with clear inhibition even at the lowest quartile. The upper most RB006 plasma concentrations (Q3 and Q4) were associated with the greatest overall reductions in thrombin generation (See Table).
Conclusions: RB006 provides a concentration dependent inhibition of thrombin generation. CAT parameters representing the kinetics and overall extent of thrombin generation were most substantially affected by RB006-even at very low RB006 plasma concentrations . These data provide guidance for selecting appropriate RB006 SC dose ranges for future studies in VTE prevention and treatment.
- © 2010 by American Heart Association, Inc.