Absorption

The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately 3 to 7%. Dabigatran etexilate is a substrate of the efflux transporter P-gp. After oral administration of dabigatran etexilate in healthy volunteers, Cmax occurs at 1 hour post-administration in the fasted state. Coadministration of PRADAXA with a high-fat meal delays the time to Cmax by approximately 2 hours but has no effect on the bioavailability of dabigatran; PRADAXA may be administered with or without food.

The oral bioavailability of dabigatran etexilate increases by 75% when the pellets are taken without the capsule shell compared to the intact capsule formulation. PRADAXA capsules should therefore not be broken, chewed, or opened before administration.

Distribution

Dabigatran is approximately 35% bound to human plasma proteins. The red blood cell to plasma partitioning of dabigatran measured as total radioactivity is less than 0.3. The volume of distribution of dabigatran is 50 to 70 L. Dabigatran pharmacokinetics are dose proportional after single doses of 10 to 400 mg. Given twice daily, dabigatran’s accumulation factor is approximately two.

Elimination

Dabigatran is eliminated primarily in the urine. Renal clearance of dabigatran is 80% of total clearance after intravenous administration. After oral administration of radiolabeled dabigatran, 7% of radioactivity is recovered in urine and 86% in feces. The half-life of dabigatran in healthy subjects is 12 to 17 hours.

Metabolism

After oral administration, dabigatran etexilate is converted to dabigatran. The cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysis to the active principal dabigatran is the predominant metabolic reaction. Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes. Dabigatran is subject to conjugation forming pharmacologically active acyl glucuronides. Four positional isomers, 1-O, 2-O, 3-O, and 4-O-acylglucuronide exist, and each accounts for less than 10% of total dabigatran in plasma.

Renal Impairment

An open, parallel-group single-center study compared dabigatran pharmacokinetics in healthy subjects and patients with mild to moderate renal impairment receiving a single dose of PRADAXA 150 mg. Based on pharmacokinetic modeling, estimated exposure to dabigatran increases with the severity of renal function impairment (Table 3). Similar findings were observed in the RE-LY trial.

Table 3 Estimated Pharmacokinetic Parameters of Dabigatran by Renal Function Renal Function CrCl (mL/min) Increase in AUC Increase in Cmax t1/2
(h)
Normal 80 1x 1x 13
Mild 50 1.5x 1.1x 15
Moderate 30 3.2x 1.7x 18

Hepatic Impairment

Administration of PRADAXA in patients with moderate hepatic impairment (Child-Pugh B) showed a large inter-subject variability, but no evidence of a consistent change in exposur