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Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct F actor X a inhibitor
Author(s) -
Kubitza Dagmar,
Roth Angelika,
Becka Michael,
Alatrach Abir,
Halabi Atef,
Hinrichsen Holger,
Mueck Wolfgang
Publication year - 2013
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12054
Subject(s) - pharmacodynamics , rivaroxaban , pharmacokinetics , medicine , prothrombin time , area under the curve , gastroenterology , pharmacology , warfarin , atrial fibrillation
Aim This study investigated the effects of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban (10 mg), an oral, direct F actor X a inhibitor. Method This single centre, non‐randomized, non‐blinded study included subjects with mild ( n = 8) or moderate hepatic impairment ( n = 8), according to the C hild– P ugh 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 F actor X a, 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. Conclusion 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.