2011 - Athens - Greece

PAGE 2011: Study design
Karl-Heinz Liesenfeld

Modeling and simulation to optimise the study design investigating the hemodialysis of dabigatran in patients with end stage renal disease (ESRD)

Karl-Heinz Liesenfeld (1), Thorsten Lehr (1), Viktoria Moschetti (2), Stephan Formella (3), Andreas Clemens (3), Alexander Staab (1), Sebastian Haertter (1)

(1) Translational Medicine, Boehringer Ingelheim, Biberach, Germany, (2) Translational Medicine, Boehringer Ingelheim, Ingelheim, Germany, (3) Clinical Development + Medical Affairs, Boehringer Ingelheim, Ingelheim, Germany

Objectives: To define a study design that allows investigation of the influence of hemodialysis on the steady state exposure of dabigatran in ESRD patients. As redistribution after stop of hemodialysis may result in a clinically relevant increase in plasma concentrations the proposed study design should especially allow a comprehensive investigation of this redistribution effect.

Methods: Based on a population pharmacokinetic (PK) model of a phase III study in patients with atrial fibrillation and on information from a dedicated phase I study where dabigatran was administered to ESRD subjects undergoing hemodialysis a PK model including dialysis clearance was developed. In a first step simulations were performed to obtain a dosing schedule for ESRD patients that leads to the same steady-state trough concentrations as in the patient population (~ 90 ng/mL). In a second step the impact of three conditions, start of hemodialysis relative to intake of dabigatran etexilate (0-10 hours (h)), dialysis clearance (100-300 mL/min), and dialysis duration (1-8 h) were simulated to elucidate their influence on exposure and on the extent of redistribution.

Results: A dosing schedule for ESRD patients resulting in an inter-dialysis (3 days) steady-state trough concentration of ~ 90 ng/mL was developed. Using a typical dialysis duration of 4 h exposure might be reduced by 60 to 75% of the initial value assuming dialysis clearance values between 160 and 240 mL/min. The extent of redistribution depends on all three investigated conditions. The later the start of the hemodialysis, the higher the dialysis clearance and the longer the duration of hemodialysis the larger was the redistribution. A hemodialysis start of 8 h after the last dose results in a redistribution effect of dabigatran which is close to the maximum effect. Nonetheless, only a relatively small redistribution effect of about 7 ng/mL was predicted. In addition the late start of hemodialysis will allow a better separation of the variability caused by absorption and by dialysis.

Conclusions: Informed by the simulation results the study design consists of a hemodialysis duration of 4 h which should result in a sufficient reduction of the dabigatran concentration and thus allows a precise estimation of the dialysis clearance without burdening ESRD subjects. The start of dialysis 8 h after the last dose should allow to describe the maximum redistribution effect and to estimate the variability in the dialysis clearance.

Reference: PAGE 20 (2011) Abstr 2001 [www.page-meeting.org/?abstract=2001]
Poster: Study design
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