Dabigatran (DAB) is an orally administered thrombin inhibitor. Both DAB and its main metabolite dabigatran acylglucuronide (DABG) have established anticoagulant effects. Here, we aimed to compare the relative anticoagulant effects of DABG and DAB in humans. Anticoagulant effects of DAB and DABG were measured in vitro using a thrombin generation assay. Additionally, their effects on other coagulation assays including PT, aPTT, TT, and fibrinogen were compared. Both DAB and DABG showed inhibitory effects on thrombin generation in a dose-dependent manner, but DABG exhibited a weaker inhibitory effect than that of DAB. The IC50 values of DAB and DABG on thrombin generation AUC were 134.1 ng/mL and 281.9 ng/mL, respectively. DABG also exhibited weaker anticoagulant effects than DAB on PT, aPTT, and TT. The results of the present study indicate that the anticoagulant effect of DABG, a main active DAB metabolite, is weaker than that of DAB.

Higher risk of major hemorrhage associated with concomitant use of dabigatran and simvastatin compared to other statins was previously reported with a suggestion of P-glycoprotein-mediated interaction. The aim of this study was to evaluate the effects of simvastatin on pharmacokinetics and anticoagulant effects of dabigatran, a direct oral anticoagulant. A total of 12 healthy subjects were enrolled in an open-label, two-period, single sequence study. Subjects were given 150 mg of dabigatran etexilate followed by 40 mg of once-daily simvastatin for seven days. Dabigatran etexilate was administered with simvastatin on the seventh day of simvastatin administration. Blood samples for pharmacokinetic and pharmacodynamic analyses were obtained until 24 h post-dose of dabigatran etexilate with or without co-administration of simvastatin. Pharmacokinetic parameters were derived from noncompartmental analysis for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide. When simvastatin was co-administered, geometric mean ratios of area under time-concentration curves for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were 1.47, 1.21, and 1.57, respectively, compared to when dabigatran etexilate was administered alone. Thrombin generation assay and coagulation assay showed similar profiles between before and after co-administration of simvastatin. This study provides evidence that simvastatin treatment plays a minor role in modulating pharmacokinetics and anticoagulant effects of dabigatran etexilate.