Presentation Highlights

At Thursday’s DOACs and Beyond: Translational Aspects Oral Communications Session, Janet Leeds, Ph.D. of Portola Pharmaceuticals Inc. presented findings on her research regarding the validation of a pharmacokinetic (PK) and pharmacodynamic (PD) model of andexanet alfa, an investigational agent used for the reversal of anticoagulation with factor Xa (FXa) inhibitor therapies.

  • This study utilized interim data from the ANNEXA-4 study to validate a model developed in healthy subjects to predict the andexanet alfa regimen necessary to reverse FXa anticoagulant therapy in patients with major bleeding.
  • The mean percent reversal of anti-FXa activity for rivaroxaban and apixaban was well predicted by the model, and continued throughout all evaluated time points for rivaroxaban and slightly outside post-4 hour time points for apixaban.
  • The model closely predicted the extent of anti-FXa reversal in patients with major bleeding.

Andexanet alfa is an investigational agent for reversal of anticoagulation by FXa inhibitors. A PK/PD model, developed in healthy subjects, predicted the andexanet alfa regimen required to reverse anticoagulation by FXa inhibitors. This study aimed to validate this model, using interim data from the ANNEXA-4 study in patients with acute major bleeding.

In ANNEXA-4, an ongoing prospective, open-label study, anticoagulated patients with bleeding received andexanet IV bolus (400 or 800 mg) followed by 120-min infusion (4 or 8 mg/min). Anti-FXa activity was measured before andexanet administration (baseline), at end of bolus (EOB), end of infusion, and 4, 8, and 12 h after infusion. The relationship between baseline anti-FXa activity and reversal in healthy subjects was derived from the PK/PD model and used to provide a predicted percent reversal for patients with acute major bleeding.

In this study, 73 patients (39 anticoagulated with apixaban; 34 anticoagulated with rivaroxaban) had plasma levels available for evaluation. The mean observed percent reversal of anti-FXa activity for rivaroxaban and apixaban was well predicted by the healthy subject PK/PD model; the point estimates fell within the 90% confidence intervals of predicted values. The percent reversal at EOB for rivaroxaban and apixaban were 74.4 [58.3-90.7] and 83.9 [75.3-92.5], respectively, compared to 76.3 and 84.1 predicted by the model. The predicted reversal fit within the observed confidence intervals through the first 4 hours for rivaroxaban and apixaban, and extended through all evaluated time points for rivaroxaban and slightly outside of post 4-hour time points for apixaban, possibly due to higher baseline anti-FXa activity levels for apixaban.

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