Pharmacokinetics and Pharmacodynamics of Dabigatran Etexilate, an Oral Direct Thrombin Inhibitor, With Coadministration of Digoxin

Abstract

This study evaluated the potential impact of concomitant digoxin on the pharmacokinetics and pharmacodynamics of dabigatran etexilate, a novel oral direct thrombin inhibitor. Healthy volunteers (n = 23) received 150 mg dabigatran etexilate twice daily on days 1 to 3 and once on day 4 in 1 period. Digoxin was given in another period as a loading dose of 0.5 mg early on day 1 and 0.25 mg in the evening of day 1 and on the mornings of days 2 to 4. In a third treatment period, dabigatran etexilate together with digoxin was given on days 1 to 4. Exposure to dabigatran was not significantly altered with concomitant digoxin-the maximum concentration (Cmax,ss ) and area under the concentration-time curve at steady state over 1 dosing interval (AUCτ,ss ) of dabigatran with and without digoxin were essentially unchanged. The pharmacokinetic profile of digoxin also remained unchanged in the presence of dabigatran etexilate. Dabigatran's anticoagulant effect, assessed by blood coagulation time assays, was not influenced by digoxin. Dabigatran etexilate and digoxin can be coadministered without the need for dose adjustment of either drug.

In Vitro Predictability of Drug-Drug Interaction Likelihood of P-Glycoprotein-Mediated Efflux of Dabigatran Etexilate Based on [I]2/IC50 Threshold

“…Exact [I] 2 /IC 50 ratio of amiodarone could not be determined due to its low solubility and/or low in vitro inhibitory potential. Among the drugs assessed, only digoxin had the [I] 2 /IC 50 ratio less than 10, which was in line with the 1.1-fold AUC increase observed clinically after coadministration of dabigatran etexilate with digoxin (Stangier et al, 2011). Although the [I] 2 /IC 50 ratio of clarithromycin was higher than 10, AUC i /AUC was ,1.25 (Pradaxa package insert, 2010).…”

Determination of dabigatran in plasma, serum, and urine samples: comparison of six methods

“…Non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran were developed to overcome the major drawbacks of vitamin K antagonists (VKAs), in particular their need for continuous effect monitoring [4]. Dabigatran etexilate is rapidly hydrolyzed to its active form dabigatran after oral administration and intestinal absorption by non-specific ubiquitous esterases in gut, blood, and liver [5,6]. Peak plasma concentration are attained 2 h after ingestion [7], and the terminal half-life time was determined to be 12-17 h in patients with normal creatinine clearance [5], allowing for a fixed daily dosing regimen without the need to routinely monitor coagulation for dose adjustment [7].…”

“…Dabigatran etexilate is rapidly hydrolyzed to its active form dabigatran after oral administration and intestinal absorption by non-specific ubiquitous esterases in gut, blood, and liver [5,6]. Peak plasma concentration are attained 2 h after ingestion [7], and the terminal half-life time was determined to be 12-17 h in patients with normal creatinine clearance [5], allowing for a fixed daily dosing regimen without the need to routinely monitor coagulation for dose adjustment [7]. Dabigatran etexilate has been approved by the European Medicines Agency and the US Food and Drug Administration for prevention and treatment of venous thromboembolism after elective hip or knee replacement surgery and for the prevention of embolic stroke and non-systemic embolism in patient with non-valvular atrial fibrillation (NVAF) [8].…”

Pharmacometric Characterization of Dabigatran Hemodialysis

“…A protein binding study with radiolabeled dabigatran showed that 35 % of the dabigatran is bound to plasma proteins over a wide concentration range [2]. The prodrug dabigatran etexilate—but not the active moiety dabigatran—is a substrate of P-glycoprotein (P-gp) [11]. …”