Abstract 11473: Dabigatran Treatment Simulation in Patients Undergoing Maintenance Hemodialysis
Background: Patients undergoing maintenance hemodialysis (HD) with atrial fibrillation (AF) are at increased risk of ischemic stroke and bleeds. At present, vitamin K antagonists, e.g. warfarin, are predominantly used for anticoagulation in this patient population. In such patients, limited data are available on the use of non-vitamin K oral anticoagulants. Dabigatran etexilate (DE) is mainly (85%) renally eliminated, thus its half-life is prolonged in renal impairment. It has been established that 4-hour HD can remove up to 60% of dabigatran from the plasma. The aim of the presented study is to evaluate the dose-exposure relationship for DE in HD patients considering different dosages and HD modalities by pharmacokinetic modeling. The resulting data could inform DE dose selection in future clinical trials.
Method: We compared modeled DE exposure at once- and twice-daily doses of 75 mg, 110 mg, 150 mg in HD patients from pre- and post-dialysis dosing, with values simulated from AF patients in the RE-LY® trial, based on a previously characterized pharmacometric model. Furthermore, variations in non-renal clearance, and several dialysis settings were simulated. Exposure (area under the curve, AUC) was compared to those from typical clinical HD settings.
Results: Twice-daily DE doses showed a 1.5- to 3.3-fold increase in AUC of dabigatran compared with a typical RE-LY® patient. A once-daily dose of 75 mg given after dialysis or 110 mg given before dialysis achieved an AUC comparable (-13.3 and +4.4%, respectively) to typical RE-LY® patients. Of the patient and dialysis variables, non-renal clearance had the highest impact on exposure (≤ 31% change). Duration of dialysis, dialysate and blood flow rate changed exposure by ≤14%.
Conclusion: Twice-daily dosing of all DE doses tested in this simulation resulted in exposures clearly above what can be seen in typical RE-LY® patients and thus might not be recommendable, although this is based on modeling only and the clinical impact is unknown. In patients undergoing maintenance HD, DE 75 mg once daily (given after dialysis) or 110 mg once daily (given before dialysis), resulted in exposure comparable to that simulated in typical RE-LY® patients.
Author Disclosures: K. Liesenfeld: None. A. Clemens: None. J. Kreuzer: None. M. Brueckmann: None. A. Ahmad: None. F. Schulze: None.
- © 2015 by American Heart Association, Inc.