496: VALIDATION OF ANDEXANET ALFA REGIMEN FOR REVERSAL OF ANTICOAGULATION IN PATIENTS WITH MAJOR BLEEDING

Learning Objectives: Andexanet alfa (coagulation factor Xa [recombinant], inactivated-zhzo) is a recombinant modified human Factor Xa (FXa) protein indicated in the US for reversal of anticoagulation in patients treated with rivaroxaban and apixaban due to major bleeding. Andexanet regimen was informed by a pharmacokinetic (PK)/pharmacodynamics (PD) model developed in phase 2 studies in healthy subjects. This analysis aimed to refine the model and validate andexanet regimen with data from bleeding patients. Methods: In ANNEXA-4, an ongoing open-label study, bleeding patients anticoagulated with a FXa inhibitor received IV andexanet 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 (EOI), and 4, 8, 12 h after infusion. For validation of andexanet regimen, percent reversal of anti-FXa activity in bleeding patients was compared with the predicted reversal determined by the PK/ PD model. The model was refined by assessing intrinsic factors (renal function, age, and body weight) on both FXa and andexanet exposure. Results: Plasma levels from 139 patients (apixaban, 76; rivaroxaban, 63) were analyzed. Mean percent reversal of anti-FXa activity at EOB and EOI for rivaroxaban and apixaban in bleeding patients were similar to the PK/PD model predicted. Observed vs predicted anti-FXa activity reversal at EOB for apixaban was 91.7% vs 94.8%, and for rivaroxaban it was 88.9% vs 87.6%; values at EOI were similarly close. After 4 h, the observed reversal fit closely for rivaroxaban, but not for apixaban (8 h, 30.6% vs 40.2%; 12 h, 32.8% vs 48.6%), possibly due to higher baseline anti-FXa activity levels in some apixaban patients. The revised model, including renal function, age, and body weight, showed similar over-prediction of reversal for apixaban at later time points. Conclusions: The PK/PD model in healthy subjects predicted the level of anticoagulation reversal by andexanet in bleeding patients assessed by anti-FXa activity and, thus, validated andexanet regimen required to reverse anticoagulation by FXa inhibitors. The refined PK/PD model confirmed over-prediction of anticoagulation reversal at later times in bleeding patients with higher levels of anticoagulation markers at baseline.