Influence of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Oral Dabigatran Etexilate An Open-Label, Parallel-Group, Single-Centre Study

Background and Objective: Dabigatran etexilate is an oral direct thrombin inhibitor in clinical development for the prevention and treatment of thromboembolic disorders Following oral administration, dabigatran etexilate is rapidly absorbed and converted into its active form, dabigatran The aim of this study was to investigate the effect of renal impairment on the pharmacokinetics and pharmacodynamics of dabigatran following administration of a single oral close of dabigatran etexilate in subjects with renal impairment (150 mg) or end-stage renal disease (ESRD) on maintenance haemodialysis (50 mg) Methods: This open-label, parallel-group, single-centre study enrolled 23 subjects with mild, moderate or severe renal impairment (creatinine clearance >50 to <= 80 to 50 and <= 30 mL/min, respectively), 6 patients with ESRD and 6 healthy subjects. Blood and urine samples were collected tip to 96 hours after dosing for determination of dabigatran pharmacokinetic and pharmacodynamic parameters Results: Compared with the values in healthy subjects, the area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) values were 1.5-, 3 2- and 6 3-fold higher in subjects with mild, moderate and severe renal impairment Changes in the maximum plasma concentration (C-max) were modest, and the time to reach the C-max was unchanged. In subjects with severe renal impairment, the mean terminal elimination half-life was doubled (28 hours vs 14 hours for control) The AUC for prolongation of pharmacodynamic parameters (the activated partial thromboplastin time and ecarin clotting time) increased in line with the pharmacokinetic changes. In patients with ESRD, the dose-normalized AUC(infinity) was approximately twice the value in the control group Haemodialysis removed 62-68% of the close Dabigatran etexilate was well tolerated in all groups Conclusions: Exposure to dabigatran is increased by renal impairment and correlates with the severity of renal dysfunction A decrease in the close and/or an increase in the administration interval in these patients may be appropriate In patients with ESRD, dabigatran can be partly removed from the plasma by haemodialysis