An Evaluation of the Pharmacokinetics and Pharmacodynamics of Oral Dabigatran Etexilate in Hemodialysis Patients
Condition: Blood Coagulation Disorders
MeSH terms: Hemostatic Disorders; Blood Coagulation Disorders
Study type: Interventional
Phase: Phase 1

Summary: 
      Patients with end stage renal disease carry a high risk for atrial fibrillation (AF) and
      require oral anticoagulant therapy for prevention of stroke. Often, the oral anticoagulant,
      warfarin sodium, is prescribed. Managing dialysis patients on warfarin can be fraught will
      difficulties given the multitude of drug and food interactions, need for frequent coagulation
      monitoring and dosage adjustment, and concern that warfarin enhances vascular calcification
      in dialysis patients. Recently, dabigatran etexilate, a direct oral thrombin inhibitor, has
      been approved for use in AF patients with normal renal function. Since many drugs are
      eliminated by the kidneys and removed from the plasma during dialysis, it is important to
      determine proper drug dosing in hemodialysis patients through evaluating pharmacokinetics.
    

Detailed description: 
      The frequency of atrial fibrillation (AF) is 10- to 20- fold higher in patients with end
      stage renal disease (ESRD) compared to the general population (1-5). Conditions contributing
      to the risk of stroke in AF are highly prevalent in ESRD patients undergoing dialysis (6). A
      large number of trials have shown the usefulness of oral anticoagulation with warfarin sodium
      for primary and secondary prevention of stroke in patients with AF (7). Despite that the
      majority of these trials excluded patients with ESRD, warfarin sodium is commonly prescribed
      in dialysis patients with AF for prevention of stroke (8). Managing dialysis patients on
      wafarin sodium is challenging given the plethora of drug and food interactions, need for
      frequent coagulation monitoring and dose adjustment and lack of large randomized clinical
      trails assessing the benefit of stroke prevention versus risk of hemorrhage in this
      population (8,9). Additionally, recent concern regarding the association between vascular
      calcification enhanced by warfarin sodium in dialysis patients highlights the need for
      alternative oral anticoagulant therapy (10,11).

      A new oral anticoagulant, dabigatran etexilate, which is a direct thrombin inhibitor, has
      been approved for prevention of stroke in patients with AF and prevention of venous
      thromboembolic events (VTE) in patients who have undergone elective total hip and knee
      replacement surgeries(12-15). Other indications under investigation include the treatment of
      VTE (16) and the treatment of thromboembolic complications following acute coronary syndromes
      (17).

      Dabigatran etexilate is an orally administered prodrug, which is rapidly absorbed and
      converted to its active form, dabigatran. Dabigatran specifically and reversibly inhibits
      thrombin which is a key enzyme required in the coagulation pathway. Dabigatran etexilate
      posses beneficial properties including: a fixed oral dosage regimen, predictable
      pharmacokinetic profile, strong association between plasma drug concentration and
      anticoagulation response, low potential for drug interactions and lack of need for routine
      coagulation monitoring (18-24). As such, dabigatran etexilate represents a possible improved
      alternative to warfarin for anticoagulation in dialysis patients with AF.

      Dabigatran etexilate has been developed using a fixed dosage regimen of 150 mg twice daily in
      AF patients with normal renal function for prevention of stroke (12). Limited information
      regarding dosing dabigatran etexilate in patients with renal impairment or ESRD exists as
      these patients were excluded from all phase III trials. Despite this, a recent small study
      investigated the pharmacokinetics of a single oral dose of dabigatran etexilate 150 mg in
      healthy patients and in patients with mild to severe renal impairment (creatinine clearance
      >50 to ≤80 , >30 to ≤50 and <30 mL/min) and dabigatran etexilate 50 mg in patients with ESRD
      requiring maintenance hemodialysis (25).

      Systemic exposure to dabigatran and corresponding coagulation response was increased by renal
      impairment and correlated with the severity of renal dysfunction suggesting that a reduced
      dose and or extended dose interval may be necessary in patients with mild to severe renal
      impairment. In the six patients that were studied, hemodialysis removed on average 62% and
      68% of the dabigatran entering the dialyzer indicating that hemodialysis can compensate for
      the impaired dabigatran renal elimination that occurs in ESRD. Unfortunately, a meaningful
      correlation between dabigatran plasma concentrations and anticoagulation activity could not
      be determined as the hemodialysis patients were on unfractionated heparin to prevent clotting
      in their dialysis circuit. Furthermore, the necessity of a post-dialysis dose to maintain
      dabigatran levels in the therapeutic range was not investigated.

      Herein, we propose a pilot study to examine the single dose pharmacokinetics and
      pharmacodynamics of dabigatran etexilate in hemodialysis patients who are receiving normal
      saline flushes for prevention of extracorporeal circuit clotting. The specific objective is
      to establish baseline correlation between plasma dabigatran concentrations versus
      anticoagulation activity over time. Our long-term objective is to develop an evidence-based
      recommendation for dabigatran dosing in hemodialysis patients.
    

Intervention name(s): Dabigatran Etexilate 110 mg
Intervention type(s): Drug
Intervention description(s): All participants will receive a single dosage of dabigatran etexilate 110 mg at the start of their 4 hour dialysis session. Blood sampling will be conducted during and up to 48 hours after participant's dialysis session.
Other intervention name(s): Dabigatran Etexilate 110 mg (Pradax)
Intervention MeSH terms: Dabigatran
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: pharmacokinetics