title: Pharmacometric characterization of dabigatran hemodialysis.
abstract: BACKGROUND
  Hemodialysis has been shown to be a useful method of decreasing dabigatran plasma levels in situations that require rapid elimination of this thrombin inhibitor. However, there is currently no clinical recommendation for the accelerated/optimized elimination of dabigatran via hemodialysis (e.g., flow rates, filter type, duration of dialysis).
  
  
  OBJECTIVE
  The primary objective of the present work was to characterize, via pharmacometric methods, the effects of different blood flow rates in hemodialysis on the pharmacokinetics of dabigatran, using data from a dedicated phase I dialysis study of end-stage renal disease (ESRD) patients. In addition, the effects of various clinically relevant hemodialysis settings were evaluated by simulation to assess their potential use in non-ESRD situations.
  
  
  METHODS
  Seven patients with ESRD were investigated in an open-label, fixed-sequence, two-period comparison trial. A population pharmacokinetic model was developed to fit the data and then used for various simulations. Data analyses were performed using NONMEM(®), Berkeley Madonna, or SAS.
  
  
  RESULTS
  The pharmacokinetics of dabigatran were best described by a two-compartment model with first-order absorption and a lag time. In addition to total body clearance in ESRD subjects, a first-order dialysis clearance was implemented which was greater than zero during hemodialysis and zero during the interdialytic periods. The relationship between the dialysis clearance and the blood flow rate was best described by the Michaels function. Simulations showed that varying clinically relevant dialysis settings such as filter properties or flow rates had only minor effects. Dialysis duration had the strongest impact on dabigatran plasma concentration. The observed geometric mean redistribution effect after hemodialysis was low (<16 %). The final model was successfully evaluated through the prediction of plasma concentrations from a case report undergoing dialysis.
  
  
  CONCLUSIONS
  This analysis allowed the influences of various hemodialysis parameters on the dabigatran plasma concentration to be predicted in detail for the first time. Dialysis duration was identified as having the strongest impact on the reduction in dabigatran plasma concentration. The model developed here can potentially serve as a tool to provide guidance when considering the use of hemodialysis in patients who have received dabigatran.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str 65, 88397 Biberach, Germany. karl-heinz.liesenfeld@boehringer-ingelheim.com
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Liesenfeld
authors.forename: Alexander
authors.initials: A
authors.lastname: Staab
authors.forename: Sebastian
authors.initials: S
authors.lastname: Härtter
authors.forename: Stephan
authors.initials: S
authors.lastname: Formella
authors.forename: Andreas
authors.initials: A
authors.lastname: Clemens
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lehr
mesh_terms: D000328:Adult; D000991:Antithrombins / Q000097:blood*; D001562:Benzimidazoles / Q000097:blood*; D003198:Computer Simulation; D000069604:Dabigatran; D005544:Forecasting; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D010314:Partial Thromboplastin Time; D011237:Predictive Value of Tests; D006435:Renal Dialysis; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D000069604:Dabigatran