Pharmacokinetic Profile of the Oral Direct Thrombin Inhibitor Dabigatran Etexilate in Healthy Volunteers and Patients Undergoing Total Hip Replacement

Abstract

Dabigatran etexilate is an oral low-molecular-weight direct thrombin inhibitor. Following oral administration, dabigatran etexilate is rapidly converted to its active form, dabigatran. The authors investigated the absorption, distribution, and elimination of a single 150-mg dose capsule formulation of dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. In an open-label, 3-way crossover study, dabigatran etexilate was administered to 18 male volunteers in the fasted state, after administration of food and with coadministration of the proton pump inhibitor, pantoprazole. In a subsequent multicenter, open-label study, 59 patients received a single dose of dabigatran etexilate, administered 1 to 3 hours following total hip replacement. In healthy volunteers, food had no effect on the extent of absorption of dabigatran etexilate, although there was reduced interindividual variability for dabigatran maximum plasma concentration and AUC(0-infinity). A decrease in the mean dabigatran AUC(0-infinity) (904 to 705 ng*h/mL) occurred with coadministration of pantoprazole. In patients undergoing total hip replacement, immediate onset of absorption was seen with the maximum plasma concentration of dabigatran occurring after 6 hours. The AUC(0-24) of dabigatran was 88% of the steady-state AUC using a preliminary tablet formulation and 106% of that seen in the healthy volunteer study. Compared with healthy volunteers, the postoperative profile was flattened with delayed peak concentrations. In summary, administration of the dabigatran etexilate capsule with food has no effect on the extent of dabigatran absorption, with a moderate decrease when coadministered with pantoprazole. Adequate plasma concentrations of dabigatran were seen with early postoperative administration of the dabigatran etexilate capsule. These pharmacokinetic characteristics confirm the suitability of this oral solid dosage form for use in future clinical trials.

Prophylaxis of Venous Thromboembolism in Knee Replacement Surgery

“…Onset of action is prompt, it has a consistent anticoagulant effect. The half-life ranges between 12 and 17 h [40] but since kidney excretion accounts for 85% elimination , half-life does increase significantly also in patients with moderate renal failure ( creatinine clearance < 50 ml/min ).…”

Anticoagulant treatment for acute pulmonary embolism: a pathophysiology-based clinical approach

“…All these agents are synthetic low-molecular-weight compounds that act as direct, selective and reversible inhibitors of a specific step in the coagulation cascade [41][42][43][44][45][46][47]. The anticoagulant effect of these agents is more predictable compared to that of heparin or vitamin K antagonists, allowing their administration in fixed doses without the need for laboratory monitoring or dose adjustment.…”

Dabigatran for prophylaxis of thromboembolic events in patients with atrial fibrillation

“…36 Dabigatran has a terminal halflife (t ½ ) of about 12-17 hours (Table 1). [36][37][38] Time curves for assays of antithrombotic activity, including activated partial thromboplastin time and thrombin and ecarin clotting times parallel plasma concentration-time curves, with values increasing rapidly and dose-dependently. The activated partial thromboplastin time assay can provide a useful qualitative assessment of anticoagulant activity but is less sensitive at supratherapeutic dabigatran levels.…”

“…38,41 Dabigatran is not metabolized by hepatic cytochrome P450 isoenzymes, does not affect the metabolism of other drugs that utilize this system, and has a low potential for drug-drug interactions. [42][43][44] Preclinical and clinical studies have shown that dabigatran etexilate, but not dabigatran, is a P-glycoprotein substrate and its bioavailability may be altered by P-glycoprotein inhibitors or inducers.…”