Apixaban in End-stage Kidney Disease : A Pharmacokinetics Study
Condition: ESRD; Anticoagulant Toxicity
MeSH terms: Kidney Diseases; Kidney Failure, Chronic
Study type: Interventional
Phase: Phase 2

Summary: 
      Apixaban is a novel oral direct factor Xa inhibitor; In patients with atrial fibrillation,
      apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less
      bleeding, and resulted in lower mortality (the ARISTOTLE trial). Given its favorable outcome
      profile compared to oral vitamin K antagonists in patients with normal kidney function and in
      patients with mild to moderate kidney disease and given the potential serious side-effects of
      oral vitamin K antagonists in end-stage kidney disease, apixaban may be an attractive
      alternative for systemic anticoagulation in dialysis patients. The pharmacokinetics of
      apixaban in end-stage renal disease is not well characterized.

      The aim of the current study is to perform single dose pharmacokinetics / pharmacodynamics
      studies in patients treated with end-stage renal disease. The primary aim is to determine
      inter-dialytic pharmacokinetics of Apixaban, secondary aims are intra-dialytic
      pharmacokinetics and dose finding. Two doses of drugs will be studies (2.5 mg and 5 mg).
      Study drug will be administered at the end of a dialysis session (part A) and at the
      beginning of a dialysis session (Part B). Six (n=6) patients are scheduled to be included for
      each part and each dose.

      Anti-Xa activity values (IIU/mL) will be converted to apixaban concentration data (ng/mL).
      Apixaban concentration-time profiles will be generated and observed values for the
      descriptive PK parameters Cmax (peak plasma concentration) and time to Cmax (Tmax) will be
      determined directly from these profiles. PK profiles will be further analyzed with
      non-compartmental analysis (NCA).
    

Detailed description: 
      RATIONALE

      Chronic Kidney Disease (CKD) is one of the epidemics of modern times. In the recent National
      Health and Nutrition Examination Survey (NHANES), the overall prevalence of CKD (stages 1 to
      4) increased from 10.0% in 1988-1994 to 13.1% in 1999-2004 (1). Mounting data point to the
      lethal synergy between chronic kidney disease (CKD) and cardiovascular disease (CVD) (2,3,4)
      Atrial fibrillation (AF) is an important co-morbid condition in patients with CKD. While
      prevalence differs from region to region, it is estimated that between 5 and 10% of dialysis
      patients have AF (5). Analyses of the US renal data system (USRDS) demonstrate that the
      prevalence of AF in patients with hemodialysis continues to rise (6). Prevalent AF is
      positively associated with all-cause mortality and stroke, similar to that of the general
      population (5).

      The choice of the optimal anticoagulation regimen for hemodialysis patients with AF is
      hampered by lack of randomized controlled trials. Observational data support the use of the
      CHADS2-score for risk stratification of AF in HD (5). Cost-utility analyses suggest that
      warfarin appears to be the optimal therapy to prevent thromboembolic stroke in hemodialysis
      patients with AF (7). These analyses however extrapolate the decrease in risk of stroke
      observed in randomized trials of oral vitamin K antagonist therapy in the general population
      (7). Both retrospective and prospective observational data however observe an increased risk
      for stroke in HD patients receiving oral vitamin K antagonist therapy for AF (8,5).

      Recent findings shed a worrisome light on the pleiotropic effects of oral vitamin K
      antagonist therapy in patients with advanced chronic kidney disease. Besides promoting
      undercarboxylation of the pro- and anticoagulant factors (II, VII, IX, X, protein S, protein
      C) several other glutamine-domain containing proteins remain undercarboxylated. Matrix-Gla
      protein is a powerful calcification inhibitor. Nonphosphorylated matrix-Gla protein has been
      associated with overall mortality and cardiovascular mortality in HD patients (9).
      Observational data suggest that patients treated with oral vitamin K antagonists demonstrate
      higher valvular and coronary calcium (10). Prospective trials currently investigate the
      effects of vitamin K supplementation on the evolution of vascular calcification in patients
      with end-stage kidney disease and on aortic valve calcifications.

      Apixaban is a novel oral direct factor Xa inhibitor; In patients with atrial fibrillation,
      apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less
      bleeding, and resulted in lower mortality (the ARISTOTLE trial) (11). An important benefit of
      apixaban as compared to other recent NOACs, e.g. dabigatran and rivaroxaban, is that the
      elimination is less dependent on kidney function as only 25% is excreted renally and 75% is
      excreted through the hepatobiliary system, with a mean elimination half-life of 8-15 hours in
      healthy adults.

      Given its favorable outcome profile compared to oral vitamin K antagonists in patients with
      normal kidney function and in patients with mild to moderate kidney disease and given the
      potential serious side-effects of oral vitamin K antagonists in end-stage kidney disease,
      apixaban may be an attractive alternative for systemic anticoagulation in dialysis patients.
      The pharmacokinetics of apixaban in end-stage renal disease is not well characterized.

      HYPOTHESIS The pharmacokinetics profile of apixaban allows safe use in patients with
      end-stage renal disease

      STUDY DESIGN Open label non-randomized phase II pharmacokinetics study.

      STUDY AIMS

      Primary:

      To determine inter-dialytic pharmacokinetics of Apixaban

      Secondary:

        -  To determine intra-dialytic pharmacokinetics of Apixaban

        -  Dose finding of apixaban in patients treated with hemodialysis

      DOSING AND TIMING Part A - interdialytic kinetics Dose titration

        1. single dose 2.5 mg post-dialysis

        2. single dose 5 mg post-dialysis As study drug is administered immediately following
           dialysis, part A will provide inter-dialytic PK data (primary aim)

      Part B - intra- plus interdialytic pharmacokinetics Dose titration

        1. single dose 2.5 mg 30 minutes pre-dialysis

        2. single dose 5 mg 30 minutes pre-dialysis As study drug is administered 30 minutes
           pre-dialysis, part B will provide intra-dialytic kinetic PK data (secondary aim). As we
           expect that study drug effect is not completely lost at the end of the dialysis session,
           we will continue sampling blood at fixed time-points after end of dialysis. These data
           may contribute to interdialytic PK (primary study aim).

      NUMBER OF STUDY PARTICIPANTS

      We aim to include 6 patients for each part and dosage:

      Part A - Interdialytic kinetics 2.5 mg N = 6 5 mg N = 6

      Part B - Intra- plus interdialytic kinetics 2.5 mg N = 6 5 mg N = 6

      Based on previous publications on single dose pharmacokinetics of apixaban in healthy
      volunteers (12), we expect that 6 patients per part will provide sufficient data to generate
      PK profiles.

      SCHEDULED BLOOD SAMPLING

      Part A - Interdialytic kinetics (post-dialysis dosing)

        -  Sampling at start of first dialysis (pre)

        -  Sampling at end of dialysis (post, t = 0)

        -  Sampling for pharmacokinetics (t =0.5, 1, 2, 4, 8, 24 hours post dialysis)

        -  Sampling at start of second dialysis (t = 44 hours)

        -  Sampling at end of second dialysis (t = 48 hours)

      Part B - Intradialytic kinetics (pre-dialysis dosing)

        -  Sampling at start of first dialysis (pre)

        -  Sampling for pharmacokinetics ( t=0.25, 0.5, 1, 1.5,2, 3,4 hours after dialysis start)

        -  Sampling at end of dialysis (post, t = 0)

        -  Sampling for pharmacokinetics (t =0.5, 1, 2, 4, 24 hours post dialysis)

        -  Sampling at start of second dialysis (t = 44 hours)

        -  Sampling at end of second dialysis (t = 48 hours)

      ANALYTICAL TECHNIQUES

      Apixaban concentrations (ng/mL) will be determined based on a calibration curve with Apixaban
      (Apixaban Calibrator and controls, Hyphen).

      Conventional anticoagulation used for hemodialysis is by heparin or low molecular weight
      heparins (LMWH). This will lead to significant interference with the proposed chromogenic
      anti-Xa activity assays. To exclude interference of anticoagulation for hemodialysis during
      the study period, the routine anticoagulation will be switched to regional citrate
      anticoagulation according to local protocol during the study period. The following will be
      applied.

        -  One week wash-out period of (low molecular weight) heparin, during which hemodialysis
           anticoagulation is according to the local regional citrate anticoagulation protocol (no
           use of (low molecular weight) heparins).

        -  During the study period hemodialysis anticoagulation is according to the local regional
           citrate anticoagulation protocol (no use of (low molecular weight) heparins).

      PHARMACOKINETICS ANALYSES

      Anti-Xa activity values (IIU/mL) will be converted to apixaban concentration data (ng/mL)
      based on the previously demonstrated linear relationship (e.g. Frost et al., 2014 - PMID:
      24697979). Apixaban concentration-time profiles will be generated and observed values for the
      descriptive PK parameters Cmax (peak plasma concentration) and time to Cmax (Tmax) will be
      determined directly from these profiles. PK profiles will be further analyzed with
      non-compartmental analysis (NCA). Briefly, the slope (λ) of the terminal phase of the
      concentration-time profile will be determined by log-linear regression on the appropriate
      number (typically at least 3) of data points. The terminal (elimination) half-life (t1/2, λ)
      will be calculated from Ln(2)/λ. The area under the curve (AUC) between administration (time
      0) and the last measurable data point (AUC0-T) will be calculated with the 'Lin up/Log down'
      trapezoidal method. The AUCT-∞ will be obtained from the last measureable concentration
      divided by λ, and will be summed with AUC0-T to obtain AUC0-∞ (total exposure). Similarly,
      after plotting plasma concentration-time products as a function of time, Area under the first
      Moment Curve (AUMC) values will be calculated. The mean residence time (MRT, h) will be
      obtained from AUMC/AUC. Mean half-life (t1/2) will be calculated as Ln(2)×MRT. Oral
      ('apparent') clearance (Cl/F) values will be obtained by dividing dose by AUC. The volume of
      distribution at steady (Vdss/F) will be obtained as MRT x Cl/F. As alternative to NCA, the
      feasibility of analyzing the data with a 1-compartmental model with first order absorption
      will be explored as well. Summary statistics will be tabulated for all relevant PK
      parameters: (i) the descriptive parameters Cmax, Tmax and AUC0-∞ (total exposure), (ii) MRT
      and mean t1/2, (iii) the primary (fundamental) PK parameters Cl/F and Vd/F. Reported
      parameters will enable appropriate comparison with previously published data on apixaban PK
      in various populations. For the purpose of dose finding, AUC0-∞ (total exposure) represents
      the key parameter.
    

Intervention name(s): apixaban
Intervention type(s): Drug
Intervention description(s): non-vitamin K oral anticoagulant (NOAC)
Other intervention name(s): Eliquis
Intervention MeSH terms: Apixaban
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Intervention model description: Single dose pharmacokinetics study
Masking: None (Open Label)
Primary purpose: Treatment