Abstract
The direct thrombin inhibitor dabigatran etexilate is currently in phase III of development for the prophylaxis and treatment of thromboembolic disorders, with three trials completed in primary venous thromboembolism (VTE) prevention. Dabigatran etexilate is an orally administered prodrug, which is rapidly absorbed and converted to the active form, dabigatran. Dabigatran has been shown to specifically and reversibly inhibit thrombin, the key enzyme in the coagulation cascade. Studies in healthy volunteers and in patients undergoing orthopaedic surgery have indicated that dabigatran has a predictable pharmacokinetic/pharmacodynamic profile, allowing for a fixed-dose regimen. Peak plasma concentrations of dabigatran are reached approximately 2 hours after oral administration in healthy volunteers, with no unexpected accumulation of drug concentrations upon multiple dosing. Excretion is predominantly via the renal route as unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes. The small differences in dabigatran pharmacokinetics associated with age and gender are attributed to variations in renal function. Additional studies have shown that the pharmacokinetic/pharmacodynamic profile of dabigatran is consistent across a range of patient populations, with no effect of moderate hepatic impairment being observed. Drug-drug interactions are not observed with concomitant administration of atorvastatin, diclofenac or digoxin. The pharmacodynamic profile of dabigatran demonstrates effective anticoagulation combined with a low risk of bleeding. Further phase III studies are ongoing, including acute VTE treatment and stroke prevention in atrial fibrillation; the results obtained so far show that dabigatran etexilate is well tolerated and effective in the treatment and prevention of thromboembolic events.
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References
Husmann M, Barton M. Therapeutical potential of direct thrombin inhibitors for atherosclerotic vascular disease. Expert Opin Investig Drugs 2007 May; 16(5): 563–7
Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997 May 24; 349(9064): 1498–504
Hyers TM. Management of venous thromboembolism: past, present, and future. Arch Intern Med 2003 Apr 14; 163(7): 759–68
Hirsh J. Heparin. N Engl J Med 1991 May 30; 324(22): 1565–74
Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004 Sep; 126(3 Suppl.): 188S–203S
Turpie AG, Bauer KA, Eriksson BI, et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002 Sep 9; 162(16): 1833–40
Wittkowsky AK. Warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and drug interactions. Semin Vasc Med 2003 Aug; 3(3): 221–30
Oldenburg J, Watzka M, Rost S, et al. VKORC1: molecular target of coumarins. J Thromb Haemost 2007; 5 Suppl. 1: 1–6
Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med 2005 Sep 8; 353(10): 1028–40
Hauptmann J, Sturzebecher J. Synthetic inhibitors of thrombin and factor Xa: from bench to bedside. Thromb Res 1999 Mar 1; 93(5): 203–41
Gustafsson D, Elg M. The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review. Thromb Res 2003 Jul 15; 109 Suppl. 1: S9–15
Wienen W, Stassen JM, Priepke H, et al. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost 2007 Jul; 98(1): 155–62
Wolzt M, Sarich TS, Eriksson UG. Pharmacokinetics and pharmacodynamics of ximelagatran. Semin Vasc Med 2005 Aug; 5(3): 245–53
Kindmark A, Jawaid A, Harbron CG, et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J. Epub 2007 May 15
AstraZeneca. AstraZeneca decides to withdraw Exanta [press release]. London: AstraZeneca, 2006 Feb 14
Hauel NH, Nar H, Priepke H, et al. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002 Apr 25; 45(9): 1757–66
Markwardt F. Hirudin as alternative anticoagulant: an historical review. Semin Thromb Hemost 2002 Oct; 28(5): 405–14
Stassen JM, Rathgen K, Zimmermann R, et al. Pharmacodynamics of the oral direct thrombin inhibitor BIBR 953 [abstract]. J Thromb Haemost 2001; 86 Suppl.: OC160
Wienen W, Stassen JM, Priepke H, et al. Antithrombotic and anticoagulant effects of the direct thrombin inhibitor dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of venous thrombosis. J Thromb Haemost 2007 Jun; 5(6): 1237–42
Wienen W, Nar H, Ries UJ, et al. Antithrombotic effects of the direct thrombin inhibitor BIBR-953ZW and its orally active prodrug BIBR-1048MS in a model of venous thrombosis in rabbits [abstract]. J Thromb Haemost 2001; 86 Suppl.: OC853
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 direct thrombin inhibitor dabigatran in elderly healthy subjects [abstract no. P2207]. J Thromb Haemost 2005; 3(Suppl. 1): P2207
Stangier J, Rathgen K, Gansser D, et al. Pharmacokinetics of BIBR 953 ZW, a novel low molecular weight direct thrombin inhibitor in healthy volunteers [abstract]. J Thromb Haemost 2001; 86 Suppl.: OC2347
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, Rathgen K, Stähle H, et al. Pharmacokinetics and pharmacodynamics of dabigatran etexilate in subjects with moderate hepatic impairment [abstract no. P-W-673; online]. XXIst Congress of the International Society of Thrombosis and Haemostasis; 2007 Jul 6–12; Geneva. Available from URL: http://isth2007.abstractsondemand.com/ [Accessed 2008 Feb 29]
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, Nehmiz G, Liesenfeld KH, et al. Pharmacokinetics of BIBR 953 ZW, the active form of the oral direct thrombin inhibitor BIBR 1048, in patients undergoing hip replacement [abstract]. J Thromb Haemost 2003; 1 Suppl 1: P1916
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, Ahnfelt L, et al. Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. J Thromb Haemost 2004 Sep; 2(9): 1573–80
Cullberg M, Eriksson UG, Wahlander K, et al. Pharmacokinetics of ximelagatran and relationship to clinical response in acute deep vein thrombosis. Clin Pharmacol Ther 2005 Apr; 77(4): 279–90
Garnett C, Liesenfeld KH, Tillmann C, et al. 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 patients [poster]. Annual Meeting of the American Association of Pharmaceutical Scientists; 2003 Nov, Salt Lake City (UT)
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, Stähle H, Rathgen K. Effect of food and pantoprazole on the bioavailability of the direct thrombin inhibitor dabigatran in healthy subjects [abstract no. P1612]. J Thromb Haemost 2005; 3(Suppl. 1): P1612
Rathgen K, Stangier J, Stähle H. Bioavailability of BIBR 953 after 150mg BIBR 1048 (oral prodrug of BIBR 953) administered as HPMC capsule relative to a gelatine capsule, ands bioavailability of the HPMC capsule under the influence of food in healthy subjects [Boehringer Ingelheim clinical study report]. Biberach (Germany): Boehringer Ingelheim Pharma GmbH and Co KG, 2004
Eriksson BI, Dahl OE, Buller HR, et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005 Jan; 3(1): 103–11
Stangier J, Stähle H, Rathgen K, et al. Coadministration of the oral direct thrombin inhibitor dabigatran etexilate and atorvastatin has little impact on the pharmacokinetics and pharmacodynamics of either drug [abstract no. P-W-671; online]. XXIst Congress of the International Society of Thrombosis and Haemostasis; 2007 Jul 6–12; Geneva. Available from URL: http://isth2007.abstractsondemand.com/ [Accessed 2008 Feb 29]
Stangier J, Stähle H, Rathgen K, et al. Coadministration of the oral direct thrombin inhibitor dabigatran etexilate and diclofenac has little impact on the pharmacokinetics of either drug [abstract no. P-T-677; online]. XXIst Congress of the International Society of Thrombosis and Haemostasis; 2007 Jul 6–12; Geneva. Available from URL: http://isth2007.abstractsondemand.com/ [Accessed 2008 Feb 29]
Stangier J, Stähle H, Rathgen K, et al. No interaction of the oral direct thrombin inhibitor dabigatran etexilate and digoxin [abstract no. P-W-672; online]. XXIst Congress of the International Society of Thrombosis and Haemostasis; 2007 Jul 6–12; Geneva. Available from URL: http://isth2007.abstractsondemand.com/ [Accessed 2008 Feb 29]
Caprini JA, Hwang E, Hantel S, et al. The oral direct thrombin inhibitor, dabigatran etexilate, is effective and safe for prevention of major venous thromboembolism following major orthopedic surgery [abstract no. O-W-050; online]. XXIst Congress of the International Society of Thrombosis and Haemostasis; 2007 Jul 6–12; Geneva. Available from URL: http://isth2007.abstractsondemand.com/ [Accessed 2008 Feb 29]
Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate is effective and safe for the extended prevention of venous thromboembolism following total hip replacement [abstract no. O-W-049; online]. XXIst Congress of the International Society of Thrombosis and Haemostasis; 2007 Jul 6–12; Geneva. Available from URL: http://isth2007.abstractsondemand.com/ [Accessed 2008 Feb 29]
Friedman RJ, Caprini JA, Comp PC, et al. Dabigatran etexilate versus enoxaparin in preventing venous thromboembolism following total knee arthroplasty [abstract no. O-W-051; online]. XXIst Congress of the International Society of Thrombosis and Haemostasis; 2007 Jul 6–12; Geneva. Available from URL: http://isth2007.abstractsondemand.com/ [Accessed 2008 Feb 29]
Samama MM, LeFlem L, Guinet C, et al. Three different patterns of calibrated automated thrombogram obtained with six different anticoagulants. J Thromb Haemost 2007; 5: 2554–6
Samama MM, Le Flem L, Guinet C, et al. Three different patterns of calibrated automated thrombogram obtained with hirudin, melagatran, dabigatran, argatroban, fondaparinux and danaparoid [abstract no. P-W-644; online]. XXIst Congress of the International Society of Thrombosis and Haemostasis; 2007 Jul 6–12; Geneva. Available from URL: http://isth2007.abstractsondemand.com/ [Accessed 2008 Feb 29]
Liesenfeld KH, Schafer HG, Troconiz IF, et al. Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. Br J Clin Pharmacol 2006 Nov; 62(5): 527–37
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Dr Stangier (Drug Metabolism and Pharmacokinetics) is an employee of Boehringer Ingelheim Pharma GmbH and Co. KG. No sources of funding were used to assist in the preparation of this review. The author has no other conflicts of interest that are directly relevant to the content of this review.
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Stangier, J. Clinical Pharmacokinetics and Pharmacodynamics of the Oral Direct Thrombin Inhibitor Dabigatran Etexilate. Clin Pharmacokinet 47, 285–295 (2008). https://doi.org/10.2165/00003088-200847050-00001
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DOI: https://doi.org/10.2165/00003088-200847050-00001