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Pharmacokinetics and Pharmacodynamics of Dabigatran Etexilate, an Oral Direct Thrombin Inhibitor, Are Not Affected by Moderate Hepatic Impairment

From Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany (Dr Stangier, H. Stähle, Dr Rathgen, Dr Roth), and PAREXEL International GmbH, Berlin, Germany (Dr Shakeri-Nejad).

The impact of moderate hepatic impairment on the pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran etexilate was evaluated in an open, parallel-group study. Healthy volunteers (n = 12) and patients with hepatic impairment (Child-Pugh classification B; n = 12) received a single oral dose of 150 mg dabigatran etexilate. The mean values for area under the concentration-time curve, terminal half-life, and renal clearance of dabigatran were comparable between patients with hepatic impairment and healthy volunteers. Conversion of the dabigatran intermediate BIBR1087 to active dabigatran was slower in patients with hepatic impairment, indicating that the liver is partly involved in bioconversion of dabigatran etexilate. However, total drug exposure was comparable between groups; therefore, this observation is of no clinical relevance with respect to the anticoagulant activity of dabigatran. The extent of dabigatran glucuronidation was unchanged by liver disease; glucuronidation capacity was maintained in moderate liver disease. The activated partial thromboplastin time, ecarin clotting time, and thrombin time relationships were essentially identical in both groups. This study shows that moderate hepatic impairment does not affect the PK/PD or safety profile of dabigatran. Therefore, patients with moderate hepatic impairment can be given dabigatran etexilate without the need for dose adjustment.

Key Words: Dabigatran etexilate • hepatic impairment • oral direct thrombin inhibitor • anticoagulant

Address for reprints: Joachim Stangier, Boehringer Ingelheim GmbH & Co. KG, Birkendorferstr 69, 88397 Biberach an der Riss, Germany.

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