Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Prior to the commencement of this study, it was already known that rivaroxaban is partially cleared via the kidneys and an influence of renal insufficiency on rivaroxaban pharmacokinetics and exposure was anticipated. WHAT THIS STUDY ADDS • As many patients in the target indications of rivaroxaban will be elderly, a precise quantitative knowledge of the influence of renal function on rivaroxaban pharmacokinetics and exposure is mandatory for adequate labelling recommendations (in the context of benefit/risk provided by phase III studies) to guide therapy. This study provided detailed insight on both rivaroxaban pharmacokinetics and pharmacodynamic behaviour in renal impairment including severely renally impaired subjects. AIM: This study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10 mg single dose), an oral, direct Factor Xa inhibitor. METHODS: Subjects (n= 32) were stratified based on measured creatinine clearance: healthy controls (≥80 ml min−1), mild (50–79 ml min−1), moderate (30–49 ml min−1) and severe impairment (<30 ml min−1). RESULTS: Renal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration–time curve (AUC) LS‐mean values were 1.44‐fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52‐fold (90% CI 1.2, 2.0; moderate) and 1.64‐fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS‐mean of the AUC for prolongation of prothrombin time were 1.33‐fold (90% CI 0.92, 1.92; mild), 2.16‐fold (90% CI 1.51, 3.10 moderate) and 2.44‐fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS‐mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50‐fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86‐fold (90% CI 1.34, 2.59) and 2.0‐fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively. CONCLUSIONS: Rivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.