Am J Nephrol. 2016;43(4):229-36. doi: 10.1159/000445328.

Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Rivaroxaban in Chronic Hemodialysis.

Dias C1, Moore KT, Murphy J, Ariyawansa J, Smith W, Mills RM, Weir MR.
  • 1Janssen Research & Development, LLC, Raritan, N.J., USA.

Abstract

BACKGROUND:

This study aimed to characterize the single-dose pharmacokinetic (PK) and pharmacodynamic (PD) profile of rivaroxaban 15 mg administered before and after dialysis in subjects with end-stage renal disease (ESRD), and to compare this profile in subjects with ESRD to that in healthy control subjects (creatinine clearance ≥80 ml/min).

METHODS:

This was an open-label, single-dose, single-center, parallel-group study of rivaroxaban in ESRD subjects who had been clinically stable on maintenance hemodialysis for ≥3 months. In 8 subjects with ESRD, a 15-mg dose of rivaroxaban was administered 2 ± 0.5 h before a hemodialysis session and repeated 7-14 days later at 3 h after a 4-h hemodialysis session. Eight healthy control subjects, matched for age, sex, and body mass index, received one 15-mg rivaroxaban dose.

RESULTS:

Compared to healthy subjects, area under the rivaroxaban plasma concentration versus time curve (AUC) increased by 56% following post-dialysis administration. Assuming similar bioavailability between groups, this reflects an approximate 35% decrease in overall drug clearance in ESRD subjects. Pre-dialysis dosing resulted in only 5% lowering of AUC versus post-dialysis dosing, confirming the minimal impact of dialysis on the PK of rivaroxaban. PD effects, as assessed by change in prothrombin time, percent factor Xa inhibition, and anti-Xa activity, were generally concordant with observed changes in plasma PK.

CONCLUSIONS:

Changes in PK and PD parameters in chronic dialysis patients were generally comparable to changes observed previously in patients with moderate-to-severe renal impairment who were not undergoing dialysis, and support use of a 15-mg dose in this patient population. © 2016 The Author(s) Published by S. Karger AG, Basel.

PMID: 27100875

 

 

Supplement:

Rivaroxaban is a potent and highly selective oral direct Factor Xa (FXa) inhibitor. Activation of Factor X to FXa plays a central role in the cascade of blood coagulation. FXa occupies a critical place in the coagulation cascade since it is at the confluence of both the intrinsic and extrinsic clotting pathways, and is the key amplification point for the generation of thrombin. One molecule of FXa is able to generate more than 1,000 molecules of thrombin due to the amplification nature of the coagulation cascade. Selective inhibitors of FXa can terminate the amplified burst of thrombin generation and prevent clot formation. Rivaroxaban is marketed under the trade name XARELTO® and has been approved for multiple indications worldwide.

Rivaroxaban displays a balanced metabolism and elimination profile in which approximately one-third of the dose is excreted unchanged by the kidneys, mainly by active renal secretion involving the transporter proteins P-gp and BCRP, and also by glomerular filtration. The remaining approximately two-thirds of the dose is excreted as inactive metabolites in both the urine and feces. Considering the percentage of the administered dose renally eliminated as unchanged drug, it was important to understand how the drug behaves in patients with various degrees of renal impairment.

This was originally assessed as a dedicated Clinical Pharmacology study conducted in subjects with either mild (CLCR 50 to 79 mL/min); moderate (CLCR 30 to 49 mL/min) or severe (CLCR 15 to 29 ml/min), renal impairment, in which the results showed increases in rivaroxaban exposure by approximately 44%, 52% and 64%, respectively, relative to subjects with normal renal function.1 However the pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in subjects with a CLCR <15 mL/min and those requiring hemodialysis were not assessed, thereby leaving a gap in our understanding of rivaroxaban in this potential patient population. This is important, as approximately one-third of outpatients with Atrial Fibrillation (AF) also have comorbid chronic kidney disease, of which, approximately 1% are classified as having end-stage renal disease (ESRD) (stage 5: CLCR <15 mL/min). Important to note is that one-sixth of elderly dialysis patients develop AF, and conversely, the incidence of AF has also been linked to developing ESRD.

Therefore another Clinical Pharmacology study was performed to characterize the single-dose PK and PD of rivaroxaban (administered as a single 15 mg dose, once before and once after dialysis) in subjects with ESRD who are on maintenance hemodialysis. The key results of which are provided in the study abstract. In addition to understanding the general changes in the PK and PD of rivaroxaban, this study gave us the opportunity to assess the amount of protein binding that occurs with rivaroxaban in this population and its impact on hemodialysis.

The extent to which a drug is removed by dialysis is largely contingent upon its physicochemical properties. For example, the ability to bind to plasma proteins is one of these important properties. When drugs bind to plasma proteins, they typically bind to albumin and/or α1-acid glycoprotein, which are both too large to cross the dialysis membrane; therefore many drugs with a high degree of protein binding are generally not dialyzable, or very little of the drug is cleared during dialysis. This is the case with rivaroxaban.

In the above mentioned study, plasma protein binding was determined in both end stage renal disease (ESRD) and healthy control subjects. To determine the extent of this binding, blood samples were taken both predose (for both healthy /control and ESRD subjects) and again after dialysis, approximately 6 hours after rivaroxaban was dosed (for ESRD subjects). The unbound fraction of rivaroxaban in predose plasma averaged 0.14 (or ~86% protein bound) in subjects with ESRD and 0.11 (or ~89% protein bound) in healthy control subjects. The unbound fraction of rivaroxaban in plasma 6 hours after dosing in the ESRD subjects averaged 0.11 (or ~89% protein bound).

Another method for determining if or how much a drug is dialyzable, is by directly measuring the amount of drug that is captured in the plasma prior to entering the dialysis machine (predialyzer arterial plasma concentration) and immediately after exiting dialysis (postdialyzer venous plasma concentration). A listing of the predialyzer arterial plasma concentrations and postdialyzer venous plasma concentrations collected hourly during hemodialysis (at approximately 2, 3, 4, and 6 hours relative to time of rivaroxaban dose administration) as well as extraction ratios are presented in Table 1. Results showed that rivaroxaban was minimally removed during a 4-hour hemodialysis session. The mean extraction ratio of rivaroxaban was 0.03 at 2 hours and peaked at 0.11 at 4 hours.

 

Table 1: Arithmetic Mean (SD) Predialyzer and Postdialyzer Plasma Rivaroxaban Concentrations and Extraction Ratios in Subjects with End-Stage Renal Disease

 

Lastly, one can also assess the dialysate fluid collected during the procedure to determine if or how much drug has been cleared. Following the administration of a single 15 mg dose of rivaroxaban with a 4-hour hemodialysis session that followed, the mean amount of rivaroxaban excreted (Ae) during dialysis was 1.84 mg, therefore approximately 12.3% of the original dose was recovered in the dialysate fluid.

All of the above support the premise that rivaroxaban is not removed by dialysis to a clinically significant extent. This is important for those patients with continued decreasing renal function or who are currently on dialysis. Additionally, as dialysis is commonly used as a modality to reverse toxic drug concentrations during an overdose, this study supports the fact that dialysis should not be used in these clinical scenarios when rivaroxaban is the target drug in the overdose.

 

References:

1 Kubitza D, Becka M, Mueck W, Halabi A, Maatouk H, Klause N, Lufft V, Wand DD, Philipp T, Bruck H: Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol 2010; 70: 703–712.

 

 

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