Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).

Aims The novel direct thrombin inhibitor (DTI), dabigatran etexilate (Boehringer Ingelheim Pharma GmbH & Co. KG), shows potential as an oral antithrombotic agent. Two double‐blind, randomized trials were undertaken to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of orally administered dabigatran etexilate in healthy male subjects. Methods Dabigatran etexilate or placebo was administered orally at single doses of 10–400 mg (n = 40) or at multiple doses of 50–400 mg three times daily for 6 days (n = 40). Plasma and urine samples were collected over time to determine the PK profile of dabigatran. PD activity was assessed by its effects on blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), reported as international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). All adverse events were recorded. Results Dabigatran etexilate was rapidly absorbed with peak plasma concentrations of dabigatran reached within 2 h of administration. This was followed by a rapid distribution/elimination phase and a terminal phase, with associated estimated half‐lives of 8–10 h and 14–17 h with single and multiple dose administrations, respectively. Dabigatran exhibited linear PK characteristics with dose‐proportional increases observed in maximum plasma concentration and area under the curve. Steady‐state conditions were reached within 3 days with multiple dosing. The mean apparent volume of distribution during the terminal phase (Vz/F) of 1860 l (range 1430–2400 l) and the apparent total clearance after oral administration (CLtot/F) of 2031 ml min−1 (range 1480–2430), were dose independent. Time curves for aPTT, INR, TT and ECT paralleled plasma concentration–time curves with values increasing rapidly and in a dose‐dependent manner. At the highest dose of 400 mg administered three times daily, maximum prolongations over baseline of 3.1 (aPTT), 3.5 (INR), 29 (TT) and 9.5‐fold (ECT) were observed. Dabigatran underwent conjugation with glucuronic acid to form pharmacologically active conjugates that accounted for approximately 20% of total dabigatran in plasma. Overall, variability in PK parameters was low to moderate, with an average interindividual coefficient of variation (CV) of approximately 30% and variability in PD parameters was low, with CV < 10%. Of the four assays, TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. Bleeding events were few and were mild‐to‐moderate in intensity, occurring only in the higher, multiple dose groups. Conclusions These data suggest that dabigatran etexilate is a promising novel oral DTI with predictable PK and PD characteristics and good tolerability. Further investigation of dabigatran etexilate for the treatment and prophylaxis of patients with arterial and venous thromboembolic disorders, acute coronary syndromes and other medical conditions is warranted.

No abstract

ABSTRACT:The pharmacokinetics and metabolism of the direct thrombin inhibitor dabigatran ( Antithrombotic therapy plays an important role in the prevention and treatment of thromboembolic disorders. However, currently available agents are subject to certain limitations. Oral vitamin K antagonists, such as warfarin, have unpredictable pharmacokinetics and show numerous drug and food interactions (Ansell et al., 2004), whereas unfractionated and low molecular weight heparins and fondaparinux require parenteral administration. An orally active direct thrombin inhibitor would offer a number of potential advantages over these agents (Weitz and Bates, 2005).Dabigatran is a reversible, competitive, direct thrombin inhibitor that has been shown to be an effective antithrombotic agent in animal models (Stassen et al., 2001; Wienen et al., 2001a,b) and to be efficacious and safe in the prevention of deep vein thrombosis in patients undergoing elective total hip or knee replacement (Eriksson et al., 2005). Dabigatran etexilate is currently in Phase III development for primary prevention of venous thromboembolism (VTE) in patients undergoing major orthopedic surgery, acute VTE treatment, and VTE secondary prevention, as well as stroke prevention in patients with atrial fibrillation. Pharmacokinetic studies in healthy volunteers and orthopedic surgery patients showed that dose-dependent concentrations of dabigatran are achieved after p.o. administration of dabigatran etexilate, with peak concentrations reached after approximately 2 h and with a slight delay up to 6 h on the day of surgery (Eriksson et al., 2004(Eriksson et al., , 2005Stangier et al., 2005).This article describes a series of in vivo and in vitro studies performed to investigate the pharmacokinetics and metabolism of dabigatran in humans. ABBREVIATIONS: Dabigatran, -alanine, N-[[2-[[[4-[[[(hexyloxy) Materials and Methods Reference

The direct thrombin inhibitor dabigatran etexilate is currently in phase III of development for the prophylaxis and treatment of thromboembolic disorders, with three trials completed in primary venous thromboembolism (VTE) prevention. Dabigatran etexilate is an orally administered prodrug, which is rapidly absorbed and converted to the active form, dabigatran. Dabigatran has been shown to specifically and reversibly inhibit thrombin, the key enzyme in the coagulation cascade. Studies in healthy volunteers and in patients undergoing orthopaedic surgery have indicated that dabigatran has a predictable pharmacokinetic/pharmacodynamic profile, allowing for a fixed-dose regimen. Peak plasma concentrations of dabigatran are reached approximately 2 hours after oral administration in healthy volunteers, with no unexpected accumulation of drug concentrations upon multiple dosing. Excretion is predominantly via the renal route as unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes. The small differences in dabigatran pharmacokinetics associated with age and gender are attributed to variations in renal function. Additional studies have shown that the pharmacokinetic/pharmacodynamic profile of dabigatran is consistent across a range of patient populations, with no effect of moderate hepatic impairment being observed. Drug-drug interactions are not observed with concomitant administration of atorvastatin, diclofenac or digoxin. The pharmacodynamic profile of dabigatran demonstrates effective anticoagulation combined with a low risk of bleeding. Further phase III studies are ongoing, including acute VTE treatment and stroke prevention in atrial fibrillation; the results obtained so far show that dabigatran etexilate is well tolerated and effective in the treatment and prevention of thromboembolic events.

Dabigatran etexilate is an oral direct thrombin inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Following oral administration, dabigatran etexilate is rapidly absorbed and converted into its active form, dabigatran. The aim of this study was to investigate the effect of renal impairment on the pharmacokinetics and pharmacodynamics of dabigatran following administration of a single oral dose of dabigatran etexilate in subjects with renal impairment (150 mg) or end-stage renal disease (ESRD) on maintenance haemodialysis (50 mg). This open-label, parallel-group, single-centre study enrolled 23 subjects with mild, moderate or severe renal impairment (creatinine clearance >50 to < or =80, >30 to < or =50 and < or =30 mL/min, respectively), 6 patients with ESRD and 6 healthy subjects. Blood and urine samples were collected up to 96 hours after dosing for determination of dabigatran pharmacokinetic and pharmacodynamic parameters. Compared with the values in healthy subjects, the area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) values were 1.5-, 3.2- and 6.3-fold higher in subjects with mild, moderate and severe renal impairment. Changes in the maximum plasma concentration (C(max)) were modest, and the time to reach the C(max) was unchanged. In subjects with severe renal impairment, the mean terminal elimination half-life was doubled (28 hours vs 14 hours for control). The AUC for prolongation of pharmacodynamic parameters (the activated partial thromboplastin time and ecarin clotting time) increased in line with the pharmacokinetic changes. In patients with ESRD, the dose-normalized AUC(infinity) was approximately twice the value in the control group. Haemodialysis removed 62-68% of the dose. Dabigatran etexilate was well tolerated in all groups. Exposure to dabigatran is increased by renal impairment and correlates with the severity of renal dysfunction. A decrease in the dose and/or an increase in the administration interval in these patients may be appropriate. In patients with ESRD, dabigatran can be partly removed from the plasma by haemodialysis.

Dabigatran demonstrated reproducible and predictable pharmacokinetic and pharmacodynamic characteristics, together with a good safety profile, when administered to healthy elderly subjects. Minor gender differences were not considered clinically relevant. The effects of pantoprazole coadministration on the bioavailability of dabigatran were considered acceptable, and dose adjustment is not considered necessary.

No abstract