Effects of Renal Impairment on the Pharmacology of Rivaroxaban (BAY 59-7939) - An Oral, Direct, Factor Xa Inhibitor.

Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. It has predictable pharmacokinetics and pharmacodynamics in healthy subjects. Approximately 30% of rivaroxaban is excreted unchanged in the urine; therefore, renal excretion is an important route of elimination. This multicenter study was performed to evaluate the effect of renal impairment on the tolerability, pharmacokinetics, and pharmacodynamics of a single oral 10 mg dose of rivaroxaban. Subjects (N=32) were allocated to one of four groups (matched by age and gender), based on calculated creatinine clearance (CrCL): ≥80 mL/min (control); 50–79 mL/min (mild impairment); 30–49 mL/min (moderate impairment); and <30 mL/min (severe impairment). Rivaroxaban was well tolerated; treatment-emergent adverse events occurred in 62.5% of control subjects, and 12.5%, 12.5%, and 37.5% of those with mild, moderate, and severe renal impairment, respectively. All adverse events were mild to moderate in severity, and resolved by the end of the study. Decreased CrCL led to increased rivaroxaban plasma concentrations: AUC was 44%, 52%, and 64% higher in subjects with mild, moderate, and severe renal impairment, respectively, compared with control subjects (p<0.05); C_max was relatively unaffected, and t_max was delayed in subjects with CrCL <50 mL/min (3 hours vs 2 hours for control). Renal clearance of rivaroxaban decreased with decreasing renal function; 29% of rivaroxaban was excreted via the urine in control subjects, compared with 20%, 13%, and 10% in those with mild, moderate, and severe renal impairment, respectively. The pharmacodynamic effects of rivaroxaban (inhibition of FXa activity and prolongation of prothrombin time [PT]) were increased with decreasing renal function. The AUC for inhibition of FXa activity increased by 50% (mild impairment), 86% (moderate impairment), and 100% (severe impairment) (p<0.01; Pearson’s correlation coefficient −0.49), and the AUC for prolongation of PT increased by 33%, 116%, and 144%, respectively (p<0.001; correlation −0.56), compared with control. The maximum effects (E_max) of rivaroxaban on inhibition of FXa activity or prolongation of PT did not differ to a relevant extent among the different groups. In conclusion, rivaroxaban plasma concentrations and, as a result, inhibition of FXa activity and prolongation of PT, are inversely correlated with CrCL. In phase II clinical studies of rivaroxaban, patients with mild or moderate renal impairment were included without dose adjustment. However, whether dose adjustment is necessary in patients with renal impairment will require investigation in future clinical trials.