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 P < .05), decreased anti-FXa activity (67.8% to 95.0% vs 7.1% reduction; all P < .05), and restored thrombin generation in 67% to 100% vs 6% of subjects (all P < .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.

Conflict of interest statement

Conflict-of-interest disclosure: G.L., J.M.L., M. Karbarz, J.C., J.T.C., and P.B.C. are current employees of Portola Pharmaceutical. V.M., A.H., U.S., M. Kitt, M.M., and S.J.H. are past employees of Portola Pharmaceuticals. D.S. has attended advisory boards for Boerhinger Ingelheim, Daiichi-Sankyo, Servier, and Portola Pharmaceuticals and has received honoraria from Bristol-Myers Squibb–Pfizer and Bayer. M.C. has attended advisory boards for Janssen, Leo Pharma, Portola Pharmaceuticals, and Asahi Kasei Pharma America and has received funding for presentations from Leo Pharma, Bayer, Celgene, Shire, and CSL Behring. M.C.’s institution has received funding for research projects from Leo Pharma.

Figures

Graphical abstract

Figure 1.

Plasma concentrations of andexanet. Plasma concentrations of andexanet alone (phase 1) (A) and in the presence of apixaban (phase 2) (B). Values are means ± SD.

Figure 2.

Apixaban unbound and total concentrations. Plasma concentrations of unbound apixaban before and after andexanet administration in cohorts 1 to 3 (A) and 4 to 6 (B), and total plasma concentration of apixaban in cohorts 1 to 3 (C) and 4 to 6 (D) of the phase 2 study. Values are means ± standard error of the mean.

Figure 3.

Anti-FXa activity and thrombin generation. Anti-FXa activity in cohorts 1 to 3 (A) and cohorts 4 to 6 (B). Thrombin generation in cohorts 1 to 3 (C) and cohorts 4 to 6 of the phase 2 study (D). All subjects had achieved steady-state concentrations of apixaban (5 mg twice a day) on day 6 prior to administration of andexanet. Values are means ± standard error of the mean. The pre-anticoagulant ranges on day 1 for thrombin generation are shown as mean ± 1 SD (light gray) and mean ± 2 SD (dark gray), respectively.

Figure 4.

D-dimer and F1+2 levels for andexanet. D-dimer levels for andexanet alone (phase 1) (A) and in the presence of apixaban (phase 2) (B). F1+2 levels for andexanet alone (phase 1) (C) and in the presence of apixaban (phase 2) (D). Values are means ± standard error of the mean. Dashed lines represent the pre-anticoagulant ranges on day 1 (mean ± 2 SD) for D-dimer and F1+2, respectively.

Figure 4.

D-dimer and F1+2 levels for andexanet. D-dimer levels for andexanet alone (phase 1) (A) and in the presence of apixaban (phase 2) (B). F1+2 levels for andexanet alone (phase 1) (C) and in the presence of apixaban (phase 2) (D). Values are means ± standard error of the mean. Dashed lines represent the pre-anticoagulant ranges on day 1 (mean ± 2 SD) for D-dimer and F1+2, respectively.