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Clinical Pharmacokinetics

, Volume 47, Issue 1, pp 47–59 | Cite as

Pharmacokinetics and Pharmacodynamics of the Direct Oral Thrombin Inhibitor Dabigatran in Healthy Elderly Subjects

  • Joachim StangierEmail author
  • Hildegard Stähle
  • Karin Rathgen
  • Reinhold Fuhr
Original Research Article

Abstract

Objectives

To investigate the pharmacokinetic and pharmacodynamic profile of dabigatran in healthy elderly subjects; to assess the intra- and interindividual variability of dabigatran pharmacokinetics in order to assess possible gender differences; and to assess the effect of pantoprazole coadministration on the bioavailability of dabigatran.

Study design and setting

Open-label, parallel-group, single-centre study, consisting of a baseline screening visit, 7-day treatment period and post-study examination visit.

Subjects and intervention

36 healthy elderly subjects (aged ≥65 years) with a body mass index of 18.5–29.9 kg/m2. Subjects were randomized to receive dabigatran etexilate either with or without coadministration of pantoprazole. Dabigatran etexilate was administered as capsules at 150 mg twice daily over 6 days and once on the morning of day 7. Pantoprazole was administered at 40 mg twice daily, starting 2 days prior to dabigatran etexilate administration and ending on the morning of day 7.

Main outcome measures

The primary pharmacokinetic measurements included the area under the plasma concentration-time curve at steady state (AUCss), maximum (Cmax,ss) and minimum (Cmin,ss) plasma concentrations at steady state, terminal half-life (t½), time to reach Cmax,ss and renal clearance of dabigatran. The secondary pharmacokinetic parameters included the mean residence time, total oral clearance and volume of distribution. The pharmacodynamic parameters measured were the blood coagulation parameters ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT).

Results

With twice-daily administration of dabigatran etexilate, plasma concentrations of dabigatran reached steady state within 2–3 days, which is consistent with a t½ of 12–14 hours. The mean (SD) peak plasma concentrations on day 4 of treatment in male and female elderly subjects were 256 ng/mL (21.8) and 255 ng/mL (84.0), respectively. The peak plasma concentrations were reached after a median of 3 hours (range 2.0–4.0 hours). Coadministration with pantoprazole decreased the average bioavailability of dabigatran (the AUCss) by 24% (day 4; 90% CI 7.4, 37.8) and 20% (day 7; 90% CI 5.2, 33.3). Intra- and interindividual pharmacokinetic variability in the overall population was low (<30% coefficient of variation), indicating that dabigatran has a predictable pharmacokinetic profile. Prolongation of the ECT and aPTT correlated with, and paralleled, the plasma concentration-time profile of dabigatran, which demonstrates a rapid onset of action without a time delay, and also illustrates the direct mode of action of the drug on thrombin in plasma. The ECT increased in direct proportion to the plasma concentration, and the aPTT displayed a linear relationship with the square root of the plasma concentration. The mean AUCss was 3–19% higher in female subjects than in male subjects, which was likely due to gender differences in creatinine clearance. The safety profile of dabigatran was good, with and without pantoprazole coadministration.

Conclusions

Dabigatran demonstrated reproducible and predictable pharmacokinetic and pharmacodynamic characteristics, together with a good safety profile, when administered to healthy elderly subjects. Minor gender differences were not considered clinically relevant. The effects of pantoprazole coadministration on the bioavailability of dabigatran were considered acceptable, and dose adjustment is not considered necessary.

Keywords

Dabigatran Interindividual Variability Pantoprazole Fondaparinux Dabigatran Etexilate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This study was funded by Boehringer Ingelheim Pharma GmbH & Co. KG (Biberach, Germany). Dr Stangier (drug metabolism and pharmacokinetics) Mrs Stähle (medical data services) and Dr Rathgen (clinical research) are employees of Boehringer Ingelheim. Dr Fuhr (study investigator) is an employee of PAREXEL International GmbH (Berlin, Germany). The authors have no other conflicts of interest that are directly relevant to the content of this study.

References

  1. 1.
    Ries UJ, Wienen W. Serine proteases as targets for antithrombotic therapy. Drugs Future 2003; 28: 355–70CrossRefGoogle Scholar
  2. 2.
    Becker RC. Understanding the dynamics of thrombin in cardiovascular disease: pathobiology and biochemistry for the clinician. Am Heart J 2005 Jan; 149 (1 Suppl.): S2–8PubMedCrossRefGoogle Scholar
  3. 3.
    Hyers TM. Management of venous thromboembolism: past, present, and future. Arch Intern Med 2003 Apr; 163(7): 759–68PubMedCrossRefGoogle Scholar
  4. 4.
    Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119 (1 Suppl.): 8S–21SPubMedCrossRefGoogle Scholar
  5. 5.
    Nutescu EA, Helgason CM, Briller J, et al. New blood thinner offers first potential alternative in 50 years: ximelagatran. J Cardiovasc Nurs 2004 Nov–Dec; 19(6): 374–83PubMedGoogle Scholar
  6. 6.
    Gladwell TD. Bivalirudin: a direct thrombin inhibitor. Clin Ther 2002 Jan; 24(1): 38–58PubMedCrossRefGoogle Scholar
  7. 7.
    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): 1757–66PubMedCrossRefGoogle Scholar
  8. 8.
    Wienen W, Nar H, Ries UJ, et al. Effects of the direct thrombin inhibitor BIBR 953 ZW and its orally active prodrug BIBR 1048 MS on experimentally-induced clot formation and template bleeding time in rats [abstract no. P761]. Thromb Haemost 2001; 85: 216Google Scholar
  9. 9.
    Wienen W, Nar H, Ries UJ, et al. Antithrombotic effects of the direct thrombin inhibitor BIBR 953 ZW and its orally active prodrug BIBR 1048 MS in a model of venous thrombosis in rabbits [abstract no. OC853]. Thromb Haemost 2001; 86: 232Google Scholar
  10. 10.
    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): 292–303PubMedCrossRefGoogle Scholar
  11. 11.
    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; 109 Suppl. 1: S9–S15PubMedCrossRefGoogle Scholar
  12. 12.
    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. Epub 2007 Nov 15Google Scholar
  13. 13.
    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): 555–63PubMedCrossRefGoogle Scholar
  14. 14.
    Haas S. Oral direct thrombin inhibition: an effective and novel approach for venous thromboembolism. Drugs 2004; 64 Suppl. 1: 7–16PubMedCrossRefGoogle Scholar
  15. 15.
    Noble RE. Drug therapy in the elderly. Metabolism 2003 Oct; 52 (10 Suppl. 2): 27–30PubMedCrossRefGoogle Scholar
  16. 16.
    Burton DG, Allen MC, Bird JL, et al. Bridging the gap: ageing, pharmacokinetics and pharmacodynamics. J Pharm Pharmacol 2005 Jun; 57(6): 671–9PubMedCrossRefGoogle Scholar
  17. 17.
    Muhlberg W, Platt D. Age-dependent changes of the kidneys: pharmacological implications. Gerontology 1999 Sep–Oct; 45(5): 243–53PubMedCrossRefGoogle Scholar
  18. 18.
    Turnheim K. Drug therapy in the elderly. Exp Gerontol 2004 Nov–Dec; 39(11-12): 1731–8PubMedCrossRefGoogle Scholar
  19. 19.
    Saltzman JR, Russell RM. The aging gut: nutritional issues. Gastroenterol Clin North Am 1998 Jun; 27(2): 309–24PubMedCrossRefGoogle Scholar
  20. 20.
    Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 1987 Dec; 15(6): 657–80PubMedGoogle Scholar
  21. 21.
    Stangier J, Rathgen K, Stähle H, et al. Coadministration of the oral direct thrombin inhibitor dabigatran etexilate and diclofenac has little impact on the pharmacokinetics of either drug [poster no. P-T-677]. XXIst Congress of the International Society on Thrombosis and Haemostasis; 2007 Jul 6–12; GenevaGoogle Scholar
  22. 22.
    Stangier J, Stähle H, Rathgen K, et al. Coadminstration of the oral direct thrombin inhibitor dabigatran etexilate and atorvastatin has little impact on the pharmacokinetics and pharmacodynamics of either drug [poster no. P-W-671]. XXIst Congress of the International Society on Thrombosis and Haemostasis; 2007 Jul 6–12; GenevaGoogle Scholar
  23. 23.
    Stangier J, Stähle H, Rathgen K, et al. No interaction of the oral direct thrombin inhibitor dabigatran etexilate and digoxin [poster no. P-W-672]. XXIst Congress of the International Society on Thrombosis and Haemostasis; 2007 Jul 6–12; GenevaGoogle Scholar
  24. 24.
    Stangier J, Rathgen K, Stähle H, et al. Pharmacokinetics and pharmacodynamics of dabigatran etexilate in subjects with moderate hepatic impairment [poster no. P-W-673]. XXIst Congress of the International Society on Thrombosis and Haemostasis; 2007 Jul 6–12; GenevaGoogle Scholar
  25. 25.
    Cullberg M, Eriksson UG, Larsson M, et al. Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease. Br J Clin Pharmacol 2001 Jan; 51(1): 71–9PubMedCrossRefGoogle Scholar
  26. 26.
    Nowak G. Clinical monitoring of hirudin and direct thrombin inhibitors. Semin Thromb Hemost 2001 Oct; 27(5): 537–41PubMedCrossRefGoogle Scholar
  27. 27.
    Carlsson SC, Mattsson C, Eriksson UG, et al. A review of the effects of the oral direct thrombin inhibitor ximelagatran on coagulation assays. Thromb Res 2005; 115(1–2): 9–18PubMedCrossRefGoogle Scholar
  28. 28.
    Fenyvesi T, Jorg I, Harenberg J. Monitoring of anticoagulant effects of direct thrombin inhibitors. Semin Thromb Hemost 2002 Aug; 28(4): 361–8PubMedCrossRefGoogle Scholar
  29. 29.
    Gosselin RC, King JH, Janatpour KA, et al. Comparing direct thrombin inhibitors using aPTT, ecarin clotting times, and thrombin inhibitor management testing. Ann Pharmacother 2004 Sep; 38(9): 1383–8PubMedCrossRefGoogle Scholar
  30. 30.
    Stangier J, Bravo ML, Hettiarachchi R, et al. Pharmacokinetics and pharmacodynamics of dabigatran in patients undergoing total hip or knee replacement in BISTRO-2 [abstract/poster no. FP40]. 18th International Congress on Thrombosis; 2004 Jun 20–24; Ljubljana, Slovenia. Pathophysiol Haemost Thromb 2003; 33 Suppl. 2: XIVGoogle Scholar
  31. 31.
    Eriksson BI, Dahl OE, Biiller HR, et al. A new oral 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; 3(1): 103–11PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Joachim Stangier
    • 1
    Email author
  • Hildegard Stähle
    • 1
  • Karin Rathgen
    • 1
  • Reinhold Fuhr
    • 2
  1. 1.Boehringer Ingelheim GmbH & Co. KGBiberach an der RissGermany
  2. 2.PAREXEL International GmbHBerlinGermany

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