P5136Analysis of patient characteristics as covariates potentially affecting pharmacokinetics, efficacy, or safety of betrixaban in the APEX study

Abstract

BACKGROUND: Betrixaban (Btx) is a direct inhibitor of factor Xa (FXa) for prevention of venous thromboembolism (VTE) in at-risk patients hospitalized for acute medical illness. A phase 3 trial (APEX) compared extended prophylaxis with Btx to enoxaparin in acute medically ill patients. OBJECTIVE(S): To analyze the potential effect of patient characteristics on population pharmacokinetics (PK) and exposure-response relationships for acute medically ill patients who received Btx in the APEX study. METHOD(S): Patients received Btx (35-42 days; n = 3,759) or enoxaparin (10 +/- 4 days; n = 3,754). The primary efficacy and safety endpoints were composite occurrence of VTE events and incidence of major bleeding; secondary endpoints included incidence of clinically relevant non-major (CRNM) bleeding. Btx dose was 80 mg PO QD (40 mg for patients with severe renal insufficiency or requiring a concomitant strong P-glycoprotein [P-gp] inhibitor). PK samples were collected at hospital discharge (Day 14 after randomization); samples were taken 0-5 hours or 10-30 hours after the most recent dose of study medication. Patient characteristics included age, sex, race, region, body weight, CrCl category, and specific P-gp inhibitor. RESULT(S): In total, 3,146 PK samples from patients who received Btx were analyzed. For the 80 mg dose, the projected concentration was 18.8 ng/mL at 2 hours post-dose and 16.1 ng/mL at 20 hours post-dose, showing a stable daily concentration level on QD dosing. Co-administration of two P-gp inhibitors (amiodarone or clarithromycin) on the day of sampling more than doubled Btx concentration to ~35 ng/mL at 20 hours post-dosing. For the 40 mg dose, the projected concentration was 7.2 ng/mL at 20 hours post-dose, indicating a greater-than-dose-proportional exposure relationship. Patient age, sex, weight, CrCl category, P-gp inhibitors, and region were identified as significant covariates affecting Btx PK. The exposure-response relationship for the primary efficacy endpoint was not significant, but the relationship between Btx concentration and major or CRNM bleeding was significant in multivariate testing (P = 0.011). CONCLUSION(S): The Btx PK profile exhibited stable serum concentrations with QD dosing. Several covariates had a 15%-20% effect on Btx concentration, but no effect on efficacy or safety. Due to increased observed concentrations, Btx dose should be adjusted to 40 mg for patients taking amiodarone or clarithromycin, but not other P-gp inhibitors. Adjustments of Btx dose should not be necessary for patients characterized by other covariates tested in this analysis.