Abstract

Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Two phase IIb, dose-finding studies with rivaroxaban for the prevention of venous thromboembolism (VTE) after total hip replacement (THR) were conducted: one with twice-daily (bid), and one with once-daily (od) rivaroxaban dosing. In the bid study, rivaroxaban total daily doses of 5–20 mg had similar efficacy and safety to enoxaparin (40 mg od), and the od study identified a dose within this range (10 mg od) as the appropriate dose for further investigation. This analysis compared the pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban when given od or bid, using non-linear, mixed-effect population modeling. The analysis was restricted to the rivaroxaban 5, 10, and 20 mg total daily dose groups from each study, and used samples from 758 patients. In both studies, rivaroxaban PK were well described by an oral, one-compartment model, and were affected by anticipated factors: age and renal function influenced clearance, and body weight influenced volume of distribution. These effects were moderate, within the variability of the patient population, and suggested that no dose adjustment would be necessary, in this population. In both studies, the maximum and minimum plasma concentrations (Cmax and Ctrough, respectively) of rivaroxaban increased dose dependently (Table). Cmax values were higher, and Ctrough values were lower, in the od study than in the bid study; however, the 90% confidence intervals for Cmax and Ctrough in the two studies overlapped. These findings are as expected, and suggest that od dosing with rivaroxaban should not expose patients to a greater risk of bleeding (at Cmax) or VTE (at Ctrough) than bid dosing. Estimates for area under the rivaroxaban plasma-concentration time curve (AUC) were 20–28% higher in the od study than the bid study. In the PD analysis, prolongation of prothrombin time correlated with rivaroxaban plasma concentrations in a linear fashion in both studies. In conclusion, this analysis of rivaroxaban in patients undergoing THR suggested that the PK and PD of rivaroxaban are predictable after od or bid dosing, allowing selection of a convenient od dosing regimen.

Median predicted rivaroxaban PK parameters in THR patients at steady state (with 90% confidence intervals)

Rivaroxaban total daily dose
Parameter5 mg10 mg20 mg
n (bid/od) 122/124 122/140 118/132 
bid Cmax (μg/L) 39.7 (29.2–73.4) 65.2 (46.2–105) 141 (101–218) 
od Cmax (μg/L) 69.0 (49–112) 124 (88.1–194) 222 (160–360) 
bid Ctrough (μg/L) 8.61 (1.71–26.5) 15.4 (4.65–46.2) 34.9 (7.85–99.7) 
od Ctrough (μg/L) 4.50 (0.7–37.7) 9.12 (1.34–37.8) 22.4 (4.3–95.7) 
bid AUC (μg·h/L) 531 (304–1188) 915 (583–1637) 1982 (1139–3757) 
od AUC (μg·h/L) 670 (377–1283) 1170 (767–2077) 2374 (1366–4858) 
Rivaroxaban total daily dose
Parameter5 mg10 mg20 mg
n (bid/od) 122/124 122/140 118/132 
bid Cmax (μg/L) 39.7 (29.2–73.4) 65.2 (46.2–105) 141 (101–218) 
od Cmax (μg/L) 69.0 (49–112) 124 (88.1–194) 222 (160–360) 
bid Ctrough (μg/L) 8.61 (1.71–26.5) 15.4 (4.65–46.2) 34.9 (7.85–99.7) 
od Ctrough (μg/L) 4.50 (0.7–37.7) 9.12 (1.34–37.8) 22.4 (4.3–95.7) 
bid AUC (μg·h/L) 531 (304–1188) 915 (583–1637) 1982 (1139–3757) 
od AUC (μg·h/L) 670 (377–1283) 1170 (767–2077) 2374 (1366–4858) 

Disclosures: WM, EM and FM are employees of Bayer HealthCare AG.; The studies this analysis was performed on were supported by Bayer HealthCare AG and Scios, Inc.

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