Pharmacometric Characterization of the Elimination of Dabigatran by Haemodialysis
Karl-Heinz Liesenfeld (1), Alexander Staab (1), Sebastian Härtter (1), Stephan Formella (2), Andreas Clemens (2,3), Thorsten Lehr (1,4)
(1) Translational Medicine, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany, (2) Clinical Development and Medical Affairs, Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany, (3) Center for Thrombosis and Hemostasis, Johannes Gutenberg University, Medical Center, Mainz, Germany, (4) Saarland University, Saarbruecken, Germany
Objectives: To characterize the effect of haemodialysis at different blood flow rates on the pharmacokinetics (PK) of dabigatran by pharmacometric approaches and to evaluate the effects of different clinically relevant haemodialysis settings in order to assess their potential impact on elimination of dabigatran.
Methods: Data analysis was based on a population PK model originally developed to optimize the design of the haemodialysis study in end-stage renal disease (ESRD) patients [1]. Data from 7 patients with 28 dialysis and 308 plasma samples were available. The model was developed to fit the data and then used for various simulations. Data analyses were performed using NONMEM® and SAS.
Results: A 2-compartment model with first-order absorption and a lag time best described the PK of dabigatran. The apparent total body dabigatran clearance in subjects with ESRD was estimated at 12.4 L/h. An apparent dialysis clearance was implemented in parallel to describe the accelerated drug clearance caused by haemodialysis (> 0 during haemodialysis; 0 during the interdialytic periods). The effect of blood flow rate was best described using the Michaels equation. It demonstrated that, by doubling the blood flow from 200 to 400 mL/min, the dialysis clearance increases by 30%, resulting in additional reduction of the dabigatran plasma concentration by about 8%. Simulations of various haemodialysis settings (eg, type of filter, dialysis flow rate and blood flow rate), variations in renal function and duration of dialysis showed that dialysis duration had the strongest impact on dabigatran concentration. Plasma concentrations are roughly halved every 4 hours under dialysis. The observations for dabigatran also showed that the average redistribution effect after dialysis was low when plasma concentrations were similar to those usually observed in nonvalvular atrial fibrillation patients. The final model successfully predicted the plasma dabigatran concentrations described in a published case report of a patient undergoing dialysis.
Conclusions: This analysis allows a detailed description of the effect of dialysis on the plasma dabigatran concentrations in ESRD patients with a normal exposure to dabigatran. Dialysis duration was identified as having the strongest impact on the reduction of plasma dabigatran concentrations and redistribution effects were consistently found to be low. The developed model might serve as a useful tool to provide guidance for optimizing the use of haemodialysis in patients where dabigatran elimination is needed.
References:
[1] Liesenfeld K-H, Lehr T, Moschetti V, Formella S, Clemens A, Staab A et al. Modeling and simulation to optimise the study design investigating the hemodialysis of dabigatran in patients with end stage renal disease (ESRD). PAGE 20 (2011) [Available from: URL: www.page-meeting.org/?abstract=2001].
