title: Dabigatran treatment simulation in patients undergoing maintenance haemodialysis.
abstract: 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 doseexposure 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.
authors.affiliation: Karl-Heinz Liesenfeld, Department of Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany, Tel.: + 49 73 51 54 76 86, Fax: + 49 73 51 83 76 86., E-mail: karl-heinz.liesenfeld@boehringer-ingelheim.com.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Liesenfeld
authors.forename: Andreas
authors.initials: A
authors.lastname: Clemens
authors.forename: Joerg
authors.initials: J
authors.lastname: Kreuzer
authors.forename: Martina
authors.initials: M
authors.lastname: Brueckmann
authors.forename: Friedrich
authors.initials: F
authors.lastname: Schulze
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage*; D019540:Area Under Curve; D001281:Atrial Fibrillation / Q000150:complications / Q000517:prevention & control*; D002545:Brain Ischemia / Q000097:blood / Q000517:prevention & control; D003198:Computer Simulation; D000069604:Dabigatran / Q000008:administration & dosage*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000188:drug therapy / Q000628:therapy*; D008297:Male; D006435:Renal Dialysis; D020521:Stroke / Q000097:blood / Q000517:prevention & control; D014812:Vitamin K / Q000097:blood
chemical_list: D000925:Anticoagulants; D014812:Vitamin K; D000069604:Dabigatran
keywords: Dabigatran; atrial fibrillation; end-stage renal disease; maintenance haemodialysis; pharmacokinetics