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Dabigatran Etexilate in Atrial Fibrillation Patients With Severe Renal Impairment: Dose Identification Using Pharmacokinetic Modeling and Simulation
Author(s) -
Lehr Thorsten,
Haertter Sebastian,
Liesenfeld KarlHeinz,
Staab Alexander,
Clemens Andreas,
Reilly Paul A.,
Friedman Jeffrey
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011417716
Subject(s) - dabigatran , atrial fibrillation , pharmacokinetics , medicine , cardiology , pharmacology , warfarin
Dabigatran, administered orally as the prodrug dabigatran etexilate (DE), is a direct thrombin inhibitor shown to be effective in the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The aim of this analysis was to derive a modeling and simulation‐based dose and dosing regimen for AF patients with severe renal failure who could potentially benefit from the use of DE. The exposure was simulated for AF patients with severe renal impairment for several combinations of doses (75, 110, 150 mg) and posologies (BID, QD, Q2D). Simulations were based on a population pharmacokinetic model derived from data from 9522 patients from the pivotal phase III study (RE‐LY). Atrial fibrillation patients with a creatinine clearance (CRCL) of < 30 to ≥ 15 mL/min treated with a dose of 75 mg DE BID have target plasma level and exposure data largely within the concentration range proven to be safe and effective in AF patients with CRCL >30 mL/min receiving 150 mg BID. This dosing algorithm was also confirmed and supported by the United States Food and Drug Administration Clinical Pharmacology Division using their model based on the data from the dedicated renal impairment study and taking into account the safety and efficacy information from RE‐LY.