Safety, pharmacokinetics, and reversal of apixaban anticoagulation with andexanet alfa

Abstract

Direct factor Xa (FXa) inhibitors lack a specific reversal agent for emergencies such as major bleeding or urgent surgery. Andexanet alfa, a modified, catalytically inactive, recombinant human FXa derivative, reverses anticoagulant effect by binding and sequestering FXa inhibitors. This original report of safety and dose-finding, phase 1 and 2 randomized, double-blind, placebo-controlled studies, investigated various doses of andexanet in healthy volunteers. Phase 1 evaluated the safety and pharmacokinetics of andexanet (n = 24) or placebo (n = 8). In phase 2, andexanet (n = 36) or placebo (n = 18) was administered following steady-state apixaban dosing (5 mg twice daily for 6 days); safety, pharmacokinetics, and pharmacodynamics were assessed. Andexanet plasma concentration increased proportionally with dose, with rapid elimination (terminal elimination half-life, 4.35-7.5 hours). Following apixaban treatment, andexanet rapidly (≤2 minutes) and dose dependently reduced unbound apixaban concentration vs placebo (51% to 89% vs 5% reduction; all < .05), decreased anti-FXa activity (67.8% to 95.0% vs 7.1% reduction; all < .05), and restored thrombin generation in 67% to 100% vs 6% of subjects (all < .01), maintaining these effects during continuous 45- and 120-minute infusions. Andexanet was well tolerated. Nine subjects had mild/moderate infusion reactions not associated with hemodynamic changes or respiratory compromise that generally resolved without intervention or dose reduction. There were no thrombotic events or other serious safety issues. In conclusion, andexanet reversed apixaban-mediated effects on pharmacodynamic markers of anticoagulation in healthy volunteers within minutes after administration and for the duration of infusion. This trial was registered at www.clinicaltrials.gov as #NCT01758432.

Andexanet Alfa: First Global Approval

“…The pharmacodynamic half-life of andexanet alfa is ≈ 1 h [36]. The reduction in anti-factor Xa levels was sustained during andexanet alfa treatment and the levels returned to placebo levels ≈ 2 h after the bolus or after the end of infusion [32–35], which was consistent with the short pharmacodynamic half-life of andexanet alfa [36]. …”

“…apixaban, rivaroxaban, betrixaban, edoxaban and enoxaparin) in healthy volunteers [32–35]. Following dosing with one of the factor Xa inhibitors, volunteers received andexanet alfa or placebo.…”

“…Following dosing with one of the factor Xa inhibitors, volunteers received andexanet alfa or placebo. Within ≈ 2 min after administration, andexanet alfa rapidly reversed the anticoagulant effects of factor Xa inhibitors, as shown by the reduction in anti-factor Xa levels and restoration of normal thrombin generation and clotting time [32–35]. The pharmacodynamic half-life of andexanet alfa is ≈ 1 h [36].…”

“…Intravenous andexanet alfa exposure increased in a dose-proportional manner at bolus doses > 30 mg in healthy subjects [35]. The mean apparent volume of distribution of andexanet alfa was ≈ 5 L [9].…”

Demystifying the Benefits and Harms of Anticoagulation for Atrial Fibrillation in Chronic Kidney Disease

“…In the idarucizumab trial, thrombotic events occurred in 5.6% of patients after receiving therapy and included deep-vein thrombosis, pulmonary embolism, left atrial thrombus, myocardial infarction, and ischemic stroke (27). In the phase 2 trials of andexanet alfa in healthy volunteers, no thromboembolic events were reported (28). However, an interim analysis of the ongoing phase 3 trial in patients with acute major bleeding reported thrombotic events in 11% and death in 12% of patients within 30 days after administration (29).…”