title: Dose-finding study of rivaroxaban in hemodialysis patients.
abstract: BACKGROUND
  Use of vitamin K antagonists for the prevention of stroke and systemic embolism in dialysis patients with nonvalvular atrial fibrillation is controversial. However, no good alternatives presently are available. The anti-factor Xa antagonist rivaroxaban is contraindicated for lack of pharmacokinetic, pharmacodynamic, and clinical data. This study aims to characterize the pharmacokinetics/pharmacodynamics of rivaroxaban in maintenance hemodialysis patients.
  
  
  METHODS
  Pharmacokinetic and pharmacodynamic study.
  
  
  METHODS
  18 maintenance hemodialysis patients without residual kidney function at 2 centers. DRUG ADMINISTRATION, OUTCOMES, & MEASUREMENTS: (1) A single dose of 10mg of rivaroxaban was administered at the end of each of 3 consecutive dialysis sessions and area under the curve (AUC) and the effect on coagulation parameters were measured for 44 hours thereafter. (2) A single dose of 10mg of rivaroxaban was given 6 to 8 hours before a dialysis session and the effect of dialysis on rivaroxaban concentrations was evaluated. (3) To assess potential accumulation, 10mg of rivaroxaban was given once daily and AUC was measured during 24 hours on days 1 and 7.
  
  
  RESULTS
  Mean AUC0-44 of rivaroxaban plasma concentrations after a single dose of 10mg was 2,072μg/L/h, mean maximum concentration was 172.6μg/L, and mean terminal elimination half-life was 8.6 hours. Dialysis had no appreciable effect on rivaroxaban plasma concentrations. Mean trough concentration after multiple daily doses of 10mg was 20.2μg/L.
  
  
  CONCLUSIONS
  Higher rivaroxaban doses and patients with substantial residual kidney function were not studied.
  
  
  CONCLUSIONS
  A 10-mg dose of rivaroxaban in hemodialysis patients without residual kidney function results in drug exposure similar as published for 20mg in healthy volunteers. Rivaroxaban is not eliminated by dialysis. There is no accumulation after multiple daily dosing. The efficacy and safety of rivaroxaban in hemodialysis patients should be the subject of a large randomized trial.
authors: Division of Nephrology and Infectious Diseases, AZ Sint-Jan Brugge, Brugge, Belgium. Electronic address: an.devriese@azsintjan.be.
authors: An S
authors: AS
authors: De Vriese
authors: Division of Nephrology, OLVZ, Aalst, Belgium.
authors: Rogier
authors: R
authors: Caluwé
authors: Department of Laboratory Medicine, OLVZ, Aalst, Belgium.
authors: Els
authors: E
authors: Bailleul
authors: Department of Public Health, Ghent University, Ghent, Belgium.
authors: Dirk
authors: D
authors: De Bacquer
authors: Department of Laboratory Medicine, AZ Sint-Jan Brugge, Brugge, Belgium.
authors: Daniëlle
authors: D
authors: Borrey
authors: Division of Nephrology, OLVZ, Aalst, Belgium.
authors: Bruno
authors: B
authors: Van Vlem
authors: Division of Nephrology and Infectious Diseases, AZ Sint-Jan Brugge, Brugge, Belgium.
authors: Stefaan J
authors: SJ
authors: Vandecasteele
authors: Department of Laboratory Medicine, AZ Sint-Jan Brugge, Brugge, Belgium.
authors: Jan
authors: J
authors: Emmerechts
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D001281:Atrial Fibrillation / Q000150:complications; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D065427:Factor Xa Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000628:therapy; D008297:Male; D009025:Morpholines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D006435:Renal Dialysis; D000069552:Rivaroxaban; D013876:Thiophenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D013923:Thromboembolism / Q000517:prevention & control; D019851:Thrombophilia / Q000188:drug therapy / Q000209:etiology
chemical_list: D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban
keywords: Hemodialysis; anti-FXa activity; anticoagulant; area under the curve (AUC); atrial fibrillation; dose adjustment; dose finding; dosing guideline; end-stage renal disease (ESRD); pharmacodynamics; pharmacokinetics; rivaroxaban; stroke