Dabigatran treatment simulation in patients undergoing maintenance haemodialysis

Karl-Heinz Liesenfeld; Andreas Clemens; Joerg Kreuzer; Martina Brueckmann; Friedrich Schulze

doi:10.1160/th15-07-0531

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 115(03): 562-569
DOI: 10.1160/th15-07-0531

Coagulation and Fibrinolysis

Schattauer GmbH

Dabigatran treatment simulation in patients undergoing maintenance haemodialysis

Authors

Karl-Heinz Liesenfeld^*

¹Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
Andreas Clemens^*

²Center for Thrombosis and Haemostasis, University Medical Centre, Mainz, Germany
Joerg Kreuzer

³Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
Martina Brueckmann

³Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

⁴Faculty of Medicine Mannheim of the University of Heidelberg, Mannheim, Germany
Friedrich Schulze

³Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

Abstract

Summary

Patients with atrial fibrillation requiring maintenance haemodialysis are at increased risk of ischaemic stroke and bleeds. Currently, vitamin K antagonists such as warfarin are predominantly used in these patients as limited data are available on the use of non-vitamin K oral anticoagulants, including dabigatran etexilate (dabigatran). Dabigatran is approximately 85 % renally eliminated, thus, its half-life is prolonged in renal impairment. This study simulated the dose-exposure relationship of dabigatran in patients undergoing haemodialysis. Dabigatran exposure was modelled at once- and twice-daily doses of 75 mg, 110 mg and 150 mg and at variations in non-renal clearance and dialysis settings. Resultant dose exposure (area under the curve [AUC]) was compared with values simulated from typical patients in the RE-LY^® trial (based on a previously characterised pharmacometric model). In this simulation, all twice-daily dosages resulted in exposures above those simulated from typical RE-LY patients (1.5- to 3.3-fold increase in AUC) and thus may not be optimal for use in haemodialysis patients. However, dabigatran doses of 75 mg or 110 mg once daily produced exposures comparable to those simulated in typical RE-LY patients (-13.3 and +4.4 %, respectively). Of patient and dialysis variables, non-renal clearance had the highest impact on exposure (≤30.8 % change). These data could potentially inform dose selection in patients undergoing maintenance haemodialysis and the findings warrant investigation in future clinical trials.

Keywords

Dabigatran - end-stage renal disease - maintenance haemodialysis - atrial fibrillation - pharmacokinetics

Full Text

References

References
1 Reinecke H, Brand E, Mesters R. et al. Dilemmas in the management of atrial fibrillation in chronic kidney disease. J Am Soc Nephrol 2009; 20: 705-711.
2 Winkelmayer WC, Patrick AR, Liu J. et al. The increasing prevalence of atrial fibrillation among hemodialysis patients. J Am Soc Nephrol 2011; 22: 349-357.
3 Boccardo P, Remuzzi G, Galbusera M. Platelet dysfunction in renal failure. Semin Thromb Hemost 2004; 30: 579-589.
4 January CT, Wann LS, Alpert JS. et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64: e1-76.
5 Boehringer Ingelheim. Pradaxa 110 mg hard capsules Summary of Product Characteristics. Electronic medicines compendium. Available at: http://www.medicines.org.uk/emc/medicine/20760 Accessed June 18, 2015.
6 Van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
7 Huisman MV, Lip GY, Diener HC. et al. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice. Thromb Haemost 2012; 107: 838-847.
8 Amdipharm Mercury Company Limited. Marevan 1 mg Tablets Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc/medicine/21562. Accessed June 18, 2015.
9 Boehringer Ingelheim Pharmaceuticals Inc. PRADAXA - dabigatran etexilate mesylate capsule Prescribing Information. Available at: http://www.accessdata.fda.gov/spl/data/9353aeac-a39c-5b3a-21fd-b1413f60301b/9353aeac-a39c-5b3a-21fd-b1413f60301b.xml. Accessed June 18, 2015.
10 Chan KE, Edelman ER, Wenger JB. et al. Dabigatran and rivaroxaban use in at-rial fibrillation patients on hemodialysis. Circulation 2015; 131: 972-979.
11 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
12 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363: 1875-1876.
13 Stangier J, Rathgen K, Stahle H. et al. Influence of renal impairment on the phar-macokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49: 259-268.
14 Khadzhynov D, Wagner F, Formella S. et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 2013; 109: 596-605.
15 Liesenfeld KH, Staab A, Haertter S. et al. Pharmacometric characterization of dabigatran hemodialysis. Clin Pharmacokinet 2013; 52: 453-462.
16 Hariharan S, Madabushi R. Clinical pharmacology basis of deriving dosing recommendations for dabigatran in patients with severe renal impairment. J Clin Pharmacol 2012; 52: 119S-125S.
17 Lehr T, Haertter S, Liesenfeld KH. et al. Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: dose identification using pharmacoki-netic modeling and simulation. J Clin Pharmacol 2012; 52: 1373-1378.
18 Kooiman J, van der Hulle T, Maas H. et al. Pharmacokinetics and pharmacody-namics of dabigatran etexilate 75 mg BID in patients with severe chronic kidney disease: prospective validation of a post hoc determined dose. Eur Heart J 2014; Suppl 1: 428.
19 Liesenfeld KH, Lehr T, Dansirikul C. et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 2011; 9: 2168-2175.
20 Arbor Research Collaborative for Health. 2012 DOPPS Annual Report. Available at: http://www dopps org/annualreport/. Accessed June 24, 2015.
21 Gambro Lundia AB. 2009 Polyflux* H - High Flux Dialyse product information.
22 Michaels AS. Operating parameters and performance criteria for hemodialyzers and other membrane-separation devices. Trans Am Soc Artif Intern Organs 1966; 12: 387-392.
23 Gambro Lundia AB. 2008 Polyflux* L product information.
24 Fresenius Medical Care. 2007 Dialysers and filters Product Range.
25 US Renal Data System. 2005 USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD:
26 Dansirikul C, Lehr T, Liesenfeld KH. et al. A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery. Thromb Haemost 2012; 107: 775-785.