The Clinical Pharmacology of Rivaroxaban, a Factor Xa inhibitor, in Chronic Hemodialysis

What is it about?

In order to understand the clinical pharmacology of rivaroxaban in patients with End Stage Renal Disease (ESRD) who were undergoing maintenance hemodialysis, a Phase I healthy volunteer (other than having renal disease) clinical trial to specifically assess the pharmacokinetic (PK) and pharmacodynamic (PD) profile of rivaroxaban was conducted. This open-label, single-dose, single-center, parallel-group study evaluated the use of rivaroxaban in subjects with ESRD who were clinically stable on maintenance hemodialysis for at least 3 months. The 2 primary objectives of this study were: (1) to characterize the single-dose PK and PD of rivaroxaban administered as a 15-mg dose, both once before and once after dialysis, in subjects with ESRD, and (2) to compare this PK and PD profile in subjects with ESRD to that in healthy control subjects with CLCR ≥80 ml/min. Additional secondary objectives included assessment of (1) the fraction of a rivaroxaban dose that is removed via hemodialysis, (2) the single-dose PDs of rivaroxaban in subjects with ESRD, and (3) the safety and tolerability of rivaroxaban in subjects with ESRD.

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Why is it important?

Rivaroxaban (JNJ 39039039, BAY 59-7939, XARELTO®) is a potent and highly selective oral direct factor Xa (FXa) inhibitor. FXa plays a central role in the prothrombinase complex that catalyzes the conversion of prothrombin to thrombin. Rivaroxaban has been approved for multiple indications worldwide. In the United States, the Food and Drug Administration approved rivaroxaban in November 2011 to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation, given as a 20-mg once-daily dose in patients with an estimated creatinine clearance (CLCR) >50 ml/min and as a 15-mg once-daily dose for patients with an estimated CLCR between 15 and 50 ml/min (Cockcroft-Gault formula. Overall, results from this study show that deterioration of renal filtration function from severe to ESRD does not have a significant impact on rivaroxaban PK and PD beyond those changes observed with either moderate or severe renal impairment. These results were determined in a population of otherwise healthy subjects with ESRD undergoing hemodialysis in standard 4-hour sessions, using a “tight (low) heparinization” schedule. Based on the results of this study, the FDA harmonized the labels across the Factor Xa inhibitors to address its use in patients with ESRD and on Dialysis. Giving physicians another option for the care of these patients.

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