Summary

• For the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the reduction in the risk of recurrence of DVT and of PE in adults: Avoid the use of XARELTO in patients with creatinine clearance (CrCl) <15 mL/min.¹
• To reduce the risk of stroke and systemic embolism with nonvalvular atrial fibrillation (AF) in adults: For patients with a CrCl ≤50 mL/min, the recommended dose of XARELTO is 15 mg once daily with the evening meal. Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO.¹
• For the prophylaxis of DVT following hip or knee replacement surgery in adults: Avoid the use of XARELTO in patients with CrCl <15 mL/min. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to 50 mL/min. Patients who develop acute renal failure while on XARELTOshould discontinue the treatment.¹
• In adults, for the prophylaxis of VTE in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding: Avoid the use of XARELTO in patients with CrCl <15 mL/min.¹
• There is no dose adjustment required based on CrCl in adult patients being treated for reduction of risk of major cardiovascular events (CV death, MI, and stroke) in chronic CAD and reduction of risk of major thrombotic vascular events in PAD, including patients after lower extremity revascularization due to symptomatic PAD.¹
• In pharmacokinetic studies, compared to healthy adult subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in adult subjects with renal impairment. Increases in pharmacodynamic effects were also observed. Please refer to section 8.6 Renal Impairment of the XARELTO full prescribing information for additional information.¹
• XARELTO is metabolized via different types of biotransformation reactions and the drug and metabolites are rapidly eliminated by renal and fecal/biliary routes.² In a phase 1 study, following administration of [¹⁴C]-XARELTO, approximately one-third (36%) was recovered as unchanged drug in the urine and 7% was recovered as unchanged drug in feces.¹
• Several studies have been conducted to evaluate the pharmacokinetics (PK) and PD of XARELTO in patients with renal insufficiency.^3-7

CLINICAL STUDIES

Dias et al 2016

Dias et al (2016)³ conducted an open-label, single-dose, single-center, parallel group study to assess the PK and PD of XARELTO in patients with ESRD who were stable on maintenance hemodialysis for at least 3 months.

• The primary objectives of the study were to characterize the PK and PD of a single 15 mg dose before and after dialysis and compare it to the PK/PD profile of normal renal function subjects with a CrCl ≥80 ml/min.
• Secondary objectives included assessing the fraction of XARELTO removed by hemodialysis, the PD of XARELTO in subjects with ESRD, and the safety and tolerability of XARELTO in ESRD patients.
• Sixteen male patients (8 with ESRD; 8 with normal renal function) were recruited. Group matching was applied to the normal renal function group to ensure a similar patient population with respect to gender, age, and body mass index.

The study consisted of a 21-day screening period followed by 2 treatment periods for the ESRD group and 1 treatment period for the normal renal function group. Blood samples were collected prior to and 72-hours following XARELTO administration. XARELTO concentrations were measured from urine samples from both groups and also from the dialysate fluid in the ESRD group. See Table: XARELTO PK Data in ESRD Compared to Normal Renal Function

• Treatment period 1 (ESRD group): single 15 mg XARELTO dose administered 2 (±0.5) hours before starting a 4-hour hemodialysis session (predialysis), followed by a washout period of 7-14 days
• Treatment period 2 (ESRD group): single 15 mg XARELTO dose administered 3 hours after completion of a 4-hour dialysis session (postdialysis)
• Treatment period 1 (normal renal function group): single 15 mg XARELTO dose

• XARELTO was found to be highly protein bound in both treatment groups.
• Patients with ESRD who were given XARELTO postdialysis had increased systemic exposure (area under the curve [AUC] 56%; 35% decreased clearance) compared with normal renal function subjects.
• Predialysis XARELTO resulted in a 5% lowering of plasma AUC compared to postdialysis administration.
• Maximum plasma concentration and AUC were lower when XARELTO was administered predialysis compared to postdialysis.
• Changes in prothrombin time, factor Xa inhibition, and anti-Xa activity were consistent with the PK changes and were higher in ESRD vs normal renal function subjects.

De Vriese et al (2015)

De Vriese et al (2015)⁴ performed a study to evaluate the PK and PD of XARELTO in maintenance hemodialysis patients.

Study Design/Methods

• Eighteen adult patients who were dialyzed 3 times weekly for at least 3 months without residual renal function were included.
• Intervention 1: evaluate XARELTO concentrations and response following a single 10 mg dose administration immediately after 3 consecutive dialysis sessions in 12 patients.
• Intervention 2: evaluate the effect of dialysis on XARELTO concentrations and response following a single 10 mg dose in the morning when dialysis was scheduled in the afternoon, or in the previous evening when dialysis was scheduled in the morning. Dialysis was scheduled 6-8 hours following the XARELTO dose.
• Intervention 3: evaluate XARELTO concentrations following a dose of 10 mg once-daily in the morning in 6 patients during 7 days.
• Safety and tolerability were also assessed.

Results

• Intervention 1 (n=12)
  • Mean area under the concentration-time curve from 0 to 44 hours (AUC_0-44) following a single oral dose of XARELTO was 2072 (range, 1141-4946) µg/L/hour with coefficient of variation (CV) of 54.7%.
  • Mean maximum plasma concentration (Cmax) was 172.6 (range, 103-394) µg/L with CV of 45.5%.
  • Mean terminal elimination half-life (t1/2) was 8.6 (range, 5.0-12.4) hours with CV of 27.3%.
• Intervention 2 (n=12)
  • Dialysis had no appreciable effect on concentrations of XARELTO. Mean concentration of XARELTO in dialysate was 5.4 ± 5.4 (standard deviation) ng/mL.
• Intervention 3 (n=6)
  • Day 1
    • Mean area under the concentration-time curve from 0 to 24 hours (AUC_0-24 ) after XARELTO 10 mg was 1449 (range, 766-2851) µg/L/h with CV of 47.6%.
    • Mean C_max was 152.8 (range, 122-239) µg/L with CV of 30.7%.
    • Mean t1/2 was 6.6 (range, 4.2-12.4) hours with CV of 48.4%.
  • Day 7
    • Mean AUC0-24 after XARELTO 10 mg was 1851 (range, 1174-2806) µg/L/hour with CV of 38.3%.
    • Mean C_max was 192.0 (range, 134-304) µg/L with CV of 31.7%.
    • Mean t1/2 was 7.3 (range, 4.3-11.8) hours with CV of 39.4%.
    • Following multiple 10 mg doses, trough plasma concentration (C_trough) was 20.2 (range, 4.1-93.4) µg/L.
• There were no serious side effects associated with XARELTO administration, and no patient-reported side effects.

Girgis et al (2014)

Girgis et al (2014)⁵ reported findings from prespecified PK and PD modeling analyses, based on matched PK and PD data obtained from a subset of patients with nonvalvular AF randomized to receive XARELTO enrolled in the ROCKET AF trial (N=161; n=25 with moderate renal impairment [CrCl 30-49 mL/min]).

• Main objectives:
  • Verify that previously developed structural population PK and PK/PD models could describe overall exposure to XARELTO and the relationship between XARELTO PK and PD (prothrombin time, prothrombinase-induced clotting time, and factor Xa activity)
  • Estimate the models’ parameters using current data from the time-matched substudy in patients with AF
  • Confirm the effect of dosing modification on exposure for moderately renally impaired patients
    • Compare 20 mg once daily dosing in patients with CrCl >50 mL/min to 15 mg once daily dosing in patients with CrCl 30-49 mL/min
• The dataset contained 801 PK samples (114 from patients with moderate renal impairment), 786 prothrombin time samples, 742 prothrombinase-induced clotting time samples, and 799 factor Xa activity samples.

PK Model

• In this study, XARELTO PK were described by an oral one-compartment model with first-order absorption.
• Patient covariates that influenced PK in this study were age and renal function (expressed as serum creatinine), which affected apparent oral clearance, and lean body mass and age, which affected apparent volume of distribution. Effects of these factors on PK parameters are noted in Table. Final Parameter Estimates from the Population PK Model in Patients with AF, Original DVT Population PK Model, and ACS Population PK Model Showing Typical (Population) Values (% SE).
  • The parameter estimates for the AF population were similar to those reported for the DVT population (dataset: 870 patients and 4634 PK samples).
  • Differences in parameters estimates between the AF population and the acute coronary syndrome population (dataset: 1347 patients and 6644 PK samples) may have been due to differing patient demographics, dissimilar covariate distributions, and/or influences of the underlying disease state on the PK of XARELTO.

Dosing Regimens

• Dose modification for patients with moderate renal impairment was confirmed. See Table. XARELTO Exposure Individual Parameter Estimates at Steady State: C_max and AUC_0-24h
  • Population-stimulated ratios (patients with moderate renal impairment:patients with mild renal impairment or normal renal function) of the means of C_max and area under the concentration-time curve from 0 to 24 hours (AUC_0-24h) fell within a prespecified statistic test range of 0.70-1.43.

Population PK/PD Model Results

• Factor Xa activity was negatively correlated with increasing plasma XARELTO concentration.
  • Age had a moderate effect on baseline parameter of the factor Xa activity model; factor Xa activity values varied approximately 30% for the age range included in the study population.
• There was a near-linear relationship between XARELTO concentration and prothrombin time and prothrombinase-induced clotting time values.
  • Inhibitory effects were observed through 24 hours postdose.
• See Table. Final Parameter Estimates for Population PK-PT and PK-PiCT Structural Models, Original DVT Population PK-PT Model, and ACS PK-PT Model Showing Typical (Population) Values (% SE)
  • An effect of renal function (expressed as CrCl) was detected in the prothrombin time and prothrombinase-induced clotting time models, with a moderate influence on base and exponent parameters.
  • Most of the parameter estimates used for the AF population were similar to those reported for the DVT population, originally used to construct the prothrombin time model, and the acute coronary syndrome population.

Kubitza et al

Kubitza et al (2010)⁶ evaluated the effect of varying degrees of renal impairment on the PK/PD and safety of a single oral dose of XARELTO (N=32).

Patients received a single oral dose of XARELTO 10 mg. Thirty-two subjects were divided into groups (n=8 in each group) according to CrCl levels: control (≥80 mL/min), mild impairment (50-79 mL/min), moderate impairment (30-49 mL/min), and severe impairment (<30 mL/min).

PK Parameters

Eighteen men and 14 women were included. The mean age was 51.8 years. Renal clearance of XARELTO decreased as the severity of renal impairment increased, which resulted in increased XARELTO plasma concentrations. AUC was 44%, 52%, and 64% higher in subjects with mild, moderate, or several renal impairment, respectively, than in control subjects (P<0.03). Although decreased renal clearance led to increased overall XARELTO exposure, the maximum plasma concentrations were relatively unaffected. The time to maximum plasma concentrations was more delayed in subjects with CrCl <50 mL/min (3 hours) than in control subjects (2 hours). The half-life of XARELTO was prolonged slightly in subjects with renal impairment (control, 8.3 hours; mild impairment, 8.7 hours; moderate impairment, 9.0 hours; severe impairment, 9.5 hours).

PD Parameters

The PD effects of XARELTO were increased as renal function decreased. The AUC for inhibition of factor Xa activity increased by 50%, 86%, and 100% in subjects with mild, moderate, or severe renal impairment, respectively, compared with the increases seen in control subjects (P=0.0067). The AUC for prolongation of prothrombin time increased by 33%, 116%, and 144% in subjects with mild, moderate, or severe renal impairment, respectively, compared with the increases seen in control subjects (P=0.0006).

Safety

Seventeen treatment-emergent adverse events, all mild or moderate in severity, were reported (control, n=5; mild impairment, n=1; moderate impairment, n=1; severe impairment, n=3). All events resolved by the end of the study, and there were no discontinuations due to adverse events.

Moore et al

Moore et al (2014)¹⁰ investigated the PK and PD of XARELTO when administered with steady-state (SS) erythromycin in patients with mild or moderate renal impairment (CrCl 50-79 mL/min and CrCl 30-49 mL/min, respectively) compared to patients with normal renal function (CrCl ≥80 mL/min).

• XARELTO PK and PD parameters were evaluated across each renal function group, with XARELTO 5 mg in subjects with mild or moderate renal impairment, and 10 mg in all subject groups, with and without concomitant SS erythromycin 500 mg 3-times daily for 6 days. The route of administration for erythromycin was not noted.
• Of 29 patients enrolled, 24 subjects (8 per renal function group) completed the study.
• XARELTO 10 mg with SS erythromycin administered together to subjects with normal renal function increased XARELTO C_max by 40% and area under the plasma concentration-time curve from time 0 to infinity (AUC_∞) by 39%.
• XARELTO 10 mg with SS erythromycin administered together in subjects with mild or moderate renal impairment increased XARELTO C_max by 56% and 64%, and AUC_∞ by 76% and 99%, respectively, relative to subjects with normal renal function.
• XARELTO 10 mg administered to subjects with mild or moderate renal impairment increased XARELTO C_max by 23% and 36%, and AUC_∞ by 15% and 17%, respectively, relative to subjects with normal renal function.
• There were no clinically significant safety issues detected during the study. The most common adverse events included abdominal pain, diarrhea and dizziness, which occurred mainly with administration of erythromycin.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 28 October 2024.