title: Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: dose identification using pharmacokinetic modeling and simulation.
abstract: 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.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Translational Medicine, D-88397 Biberach an der Riss, Germany. thorsten.lehr@boehringer-ingelheim.com
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lehr
authors.forename: Sebastian
authors.initials: S
authors.lastname: Haertter
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Liesenfeld
authors.forename: Alexander
authors.initials: A
authors.lastname: Staab
authors.forename: Andreas
authors.initials: A
authors.lastname: Clemens
authors.forename: Paul A
authors.initials: PA
authors.lastname: Reilly
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Friedman
mesh_terms: D000991:Antithrombins / Q000097:blood; D019540:Area Under Curve; D001281:Atrial Fibrillation / Q000097:blood / Q000188:drug therapy*; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D003198:Computer Simulation; D000069604:Dabigatran; D006801:Humans; D007674:Kidney Diseases / Q000097:blood / Q000188:drug therapy*; D008954:Models, Biological; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D000991:Antithrombins; D001562:Benzimidazoles; D011355:Prodrugs; D011725:Pyridines; D015091:beta-Alanine; D000069604:Dabigatran