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

From Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany (Dr Stangier, Dr Nehmiz, Dr Rathgen, H. Stähle); Departments of Orthopaedic Surgery, Sahlgrenska University Hospital/Östra, Göteborg, Sweden (Dr Eriksson); Department of Orthopaedics, Buskerud Central Hospital, Drammen, Norway (Dr Dahl); Orthopedic Department, North Älvsborgs Hospital, Trollhättan, Sweden (Dr Ahnfelt); and Boehringer Ingelheim, Sweden (R. Svärd).

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-. A decrease in the mean dabigatran AUC_0- (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.

Key Words: Dabigatran etexilate • direct thrombin inhibitor • pharmacokinetics • total hip replacement • venous thromboembolism

Address for reprints: Joachim Stangier, PhD, Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Strasse, Biberach an der Riss, D-88397, Germany.

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