Abstract
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 dose 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, >30 to ≤50 and ≤30 mL/min, respectively), 6 patients with ESRD and 6 healthy subjects. Blood and urine samples were collected up 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∞) 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 (Cmax) were modest, and the time to reach the Cmax 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∞ was approximately twice the value in the control group. Haemodialysis removed 62–68% of the dose. 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 dose 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.
References
Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008 Feb; 36(2): 386–99
Stangier J, Rathgen K, Stähle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007 Sep; 64(3): 292–303
Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 2005 May; 45(5): 555–63
Stangier J, Stähle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47(1): 47–59
Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47(5): 285–95
Garnett C, Liesenfeld KH, Tillmann C. Modelling and clinical trial simulation in drug development: the effect of renal impairment on the exposure-response relationship of a direct thrombin inhibitor, BIBR 1048, in hip replacement [abstract]. Annual Meeting of the American Association of Pharmaceutical Scientists; 2003 Oct 26–30; Salt Lake City (UT)
Troconiz IF, Tillmann C, Liesenfeld KH, et al. Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery. J Clin Pharmacol 2007 Mar; 47(3): 371–82
Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007 Sept 15; 370(9591): 949–56
Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs sub-cutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Hae-most 2007 Aug 24; 5(11): 2178–85
RE-MOBILIZE Writing Committee, Ginsberg JS, Davidson BL, Comp PC, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009 Jan; 24(1): 1–9
Ezekowitz MD, Connolly S, Parekh A, et al. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J 2009 May; 157(5): 805–10, 810.e1-2
Center for Drug Evaluation and Research, US FDA. Guidance for industry: pharmacokinetics in patients with impaired renal function — study design, data analysis, and impact on dosing and labeling [online]. Rockville (MD): FDA, 1998 May. Available from URL: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072127.pdf [Accessed 2009 Dec 17]
Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999 Mar 16; 130(6): 461–70
Eriksson UG, Johansson S, Attman PO, et al. Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran. Clin Pharmacokinet 2003; 42(8): 743–53
Hervé F, Urien S, Albengres E, et al. Drug binding in plasma: a summary of recent trends in the study of drug and hormone binding. Clin Pharmacokinet 1994; 26(1): 44–58
Zini R, Riant P, Barre J, et al. Disease-induced variations in plasma protein levels: implications for drug dosage regimens (part I). Clin Pharmacokinet 1990 Aug; 19(2): 147–59
Zini R, Riant P, Barre J, et al. Disease-induced variations in plasma protein levels: implications for drug dosage regimens (part II). Clin Pharmacokinet 1990 Sep; 19(3): 218–29
Boehringer Ingelheim Pharma GmbH & Co. KG. Pradaxa: summary of product characteristics. Ingelheim am Rhein: Boehringer Ingelheim Pharma GmbH & Co. KG, 2008 Mar [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/pradaxa/emea-combined-h829en.pdf [Accessed 2010 Jan 15]
Acknowledgements
This study was sponsored by Boehringer Ingelheim, Germany. The sponsor was responsible for the design and conduct of the study, and the collection and management of the data. The authors were responsible for the analysis and interpretation of the data and the preparation of the manuscript. The expert technical assistance of Karin Hörmann, Isolde Holzschuh and Barbara Rapp is gratefully acknowledged.
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Stangier, J., Rathgen, K., Stähle, H. et al. Influence of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Oral Dabigatran Etexilate. Clin Pharmacokinet 49, 259–268 (2010). https://doi.org/10.2165/11318170-000000000-00000
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DOI: https://doi.org/10.2165/11318170-000000000-00000