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

Journal of Clinical Pharmacology - Tập 45 Số 5 - Trang 555-565 - 2005
Joachim Stangier1, Bengt I. Eriksson2, Ola E. Dahl3, L Ahnfelt4, Gerhard Nehmiz1, Hildegard Stähle1, Karin Rathgen1, Robbyna Svärd5
1Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
2Departments of Orthopaedic Surgery, Sahlgrenska University Hospital/Östra, Göteborg, Sweden
3Department of Orthopaedics, Buskerud Central Hospital, Drammen, Norway
4Orthopedic Department, North Älvsborgs Hospital, Trollhättan, Sweden
5Boehringer Ingelheim, Sweden

Tóm tắt

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 AUC0‐∞. A decrease in the mean dabigatran AUC0‐∞ (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 AUC0–24 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.

Từ khóa


Tài liệu tham khảo

10.1001/archinte.163.7.759

10.1378/chest.126.3_suppl.204S

10.1021/jm0109513

Stassen JM, 2001, Ex vivo anticoagulant activity of BIBR 953 ZW, a novel synthetic direct thrombin inhibitor and of its prodrug BIBR 1048 MS in different animal species [abstract P763], Thromb Haemost., 86, 216

Wienen W, 2001, Effects of the direct thrombin inhibitor BIBR 953 ZW and its orally active prodrug BIBR 1048 MS on experimentally‐induced clot formation and template bleeding time in rats [abstract P761], Thromb Haemost., 85, 216

Wienen W, 2001, Antithrombotic effects of the direct thrombin inhibitor BIBR 953 ZW and its orally active prodrug BIBR 1048 MS in a model of venous thrombosis in rabbits [abstract OC853], Thromb Haemost., 86, 232

10.1111/j.1538-7836.2004.00890.x

10.1001/archinte.160.14.2199

10.1001/archinte.162.16.1833

10.1016/S0140-6736(02)11469-3

10.1161/hc2601.091386

Diletti E, 1992, Sample size determination for bioequivalence assessment by means of confidence intervals, Int J Clin Pharmacol Ther Toxicol, 30, S51

10.1007/BF01068419

10.1378/chest.126.3_suppl.338S

10.1111/j.1538-7836.2004.01100.x

Thông tin
Thông tin xuất bản

Journal of Clinical Pharmacology

Tập 45 Số 5

555-565

Thông tin tác giả