title: Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct Factor Xa inhibitor.
abstract: OBJECTIVE
  This study investigated the effects of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban (10 mg), an oral, direct Factor Xa inhibitor.
  
  
  METHODS
  This single centre, non-randomized, non-blinded study included subjects with mild (n = 8) or moderate hepatic impairment (n = 8), according to the Child-Pugh classification, and gender-matched healthy subjects (n = 16).
  
  
  RESULTS
  Rivaroxaban was well tolerated irrespective of hepatic function. Mild hepatic impairment did not significantly affect the pharmacokinetics or pharmacodynamics of rivaroxaban, compared with healthy subjects. However, in subjects with moderate hepatic impairment, total body clearance was decreased, leading to a significant increase in the area under the plasma concentration-time curve (AUC). The least-squares (LS)-mean values for AUC were 1.15-fold [90% confidence interval (CI) 0.85, 1.57] and 2.27-fold (90% CI 1.68, 3.07) higher in subjects with mild and moderate hepatic impairment, respectively, than in healthy subjects. Consequently, the pharmacodynamic responses were significantly enhanced in subjects with moderate hepatic impairment. For inhibition of Factor Xa, increases in the area under the effect-time curve and the maximum effect were observed, with LS-mean ratios of 2.59 and 1.24, respectively, vs. healthy subjects. Prolongation of prothrombin time was similar in healthy subjects and those with mild hepatic impairment, but was significantly enhanced in those with moderate hepatic impairment.
  
  
  CONCLUSIONS
  Moderate (but not mild) hepatic impairment reduced total body clearance of rivaroxaban after a single 10 mg dose, leading to increased rivaroxaban exposure and pharmacodynamic effects.
authors.affiliation: Clinical Pharmacology, Bayer Pharma AG, Wuppertal, Germany. dagmar.kubitza@bayer.com
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kubitza
authors.forename: Angelika
authors.initials: A
authors.lastname: Roth
authors.forename: Michael
authors.initials: M
authors.lastname: Becka
authors.forename: Abir
authors.initials: A
authors.lastname: Alatrach
authors.forename: Atef
authors.initials: A
authors.lastname: Halabi
authors.forename: Holger
authors.initials: H
authors.lastname: Hinrichsen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueck
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D016022:Case-Control Studies; D065427:Factor Xa Inhibitors; D005260:Female; D048550:Hepatic Insufficiency / Q000503:physiopathology*; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009025:Morpholines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D011073:Polyamines; D011517:Prothrombin Time; D000069552:Rivaroxaban; D000069603:Sevelamer; D013876:Thiophenes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009025:Morpholines; D011073:Polyamines; D013876:Thiophenes; D000069552:Rivaroxaban; D000069603:Sevelamer