A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery

Abstract

Dabigatran etexilate is the orally bioavailable pro-drug of dabigatran, a direct thrombin inhibitor. Using data from eight clinical studies in healthy volunteers and patients with non-valvular atrial fibrillation (AF) or undergoing orthopaedic surgery (OS), population pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to investigate whether the PK and PD of dabigatran differ across different populations. In both healthy volunteers (n=80) and patients (n=1,965), the PK of dabigatran was best described by a two-compartment disposition model with first-order absorption and elimination. Renal function was the only covariate shown to have a clinically relevant impact on dabigatran exposure. The patient PK model was successfully applied in predicting exposure observed in the RE-LY trial evaluating dabigatran treatment in patients with non-valvular AF. The relationship between dabigatran plasma concentrations and activated partial thromboplastin time in healthy volunteers and patients (n=762) was best described with a combination of a linear model and a maximum effect (Emax) model, consistent with previous reports. PK/PD relationships were robust across the various populations tested and were not affected by any of the covariates examined. In summary, the PK of dabigatran is sufficiently consistent to allow extrapolation of data generated in healthy volunteers to patients with AF or undergoing OS.

Pharmacometric Characterization of Dabigatran Hemodialysis

“…This agrees well with results from a healthy volunteers in a phase I study in which about 85 % of the dabigatran dose was eliminated renally in non-ESRD subjects [2]. The absorption and distribution processes of dabigatran in ESRD patients were comparable to those in healthy subjects [7]. The 21-h dosing interval during the study caused variations in food intake on days 2 and 3 in relation to dabigatran administration.…”

“…In previous analyses, the relationship between CL CR and dabigatran clearance was described by a hockey-stick or an E max model [7, 9]. In the analysis presented here, no relationship could be established between dabigatran clearance and the serum creatinine or CL CR measurements of the ESRD subjects.…”

“…First, the number of study subjects was relatively small ( n  = 7), with a total of 28 hemodialysis sessions. Nevertheless, all parameters were estimated precisely, and the absorption and distribution processes of dabigatran in ESRD patients were comparable to those in healthy subjects [7]. Secondly, all study subjects were male Caucasians in the therapeutic concentration range.…”

“…Dabigatran is eliminated mainly (85 % of the dose) via renal glomerular filtration [2, 7–10], whereby 80 % is excreted unchanged and 20 % is eliminated as glucuronide. A protein binding study with radiolabeled dabigatran showed that 35 % of the dabigatran is bound to plasma proteins over a wide concentration range [2].…”

From laboratory to clinical practice: Dabigatran effects on thrombin generation and coagulation in patient samples

“…Due to what is considered predictable pharmacokinetics, routine laboratory monitoring is claimed to be unnecessary [1,2]. Nevertheless, under special circumstances, e.g.…”