Rapid onset and offset of action of otamixaban, a potent direct intravenous factor Xa inhibitor

Abstract

Purpose: Otamixaban (otam) is a synthetic, specific and reversible direct intravenous (IV) factor Xa inhibitor. The onset/offset of action of otam at doses in the range evaluated in the phase 3 study Treatment of Acute coronary syndromes (ACS) with Otamixaban (TAO) in non-ST-elevation ACS patients planned for early invasive strategy, was investigated using phase 1 data. Methods: Onset of action was estimated by time to reach steady state plasma concentrations in healthy subjects receiving a 0.080 mg/kg IV bolus otam + a 0.100 mg/kg/h (dose 1) or 0.140 mg/kg/h (dose 2) 24h IV infusion. Offset of action was evaluated by comparing the decline of residual otam concentrations post-infusion with the return of activated partial thromboplastin time (aPTT) to baseline after a 24h IV infusion of dose 1 or 0.150 mg/kg/h (dose 3) after an initial bolus. Results: At dose 1, otam concentrations reached steady state within 15 min of IV bolus/infusion start and were stable throughout the infusion (Figure 1). At dose 2, otam concentrations reached 73% steady state 15 min after treatment start. Within 1h post-infusion, residual concentrations of otam were 36% steady state for doses 1 and 2, and were 22% (dose 1) and 21% (dose 2) steady state by 2h post-infusion. aPTT paralleled the otam concentrations with rapid prolongation early after bolus. Within 1h post-infusion, aPTT dropped from ∼1.5 to 1.1-fold and 1.6 to 1.2-fold over baseline at doses 1 and 3, respectively. aPTT returned to baseline 2h post-infusion. ![Figure][1] Figure 1 Conclusions: Otamixaban at doses in the range evaluated in TAO enables rapid attainment of steady state after treatment initiation. aPTT prolongation effects rapidly disappeared post-infusion, coinciding with a rapid drop in otam concentration. This confirms the quick onset/offset properties of otam. [1]: pending:yes