Objectives: To investigate the pharmacokinetic and pharmacodynamic profile of dabigatran in healthy elderly subjects; to assess the intra- and interindividual variability of dabigatran pharmacokinetics in order to assess possible gender differences; and to assess the effect of pantoprazole coadministration on the bioavailability of dabigatran.
Study design and setting: Open-label, parallel-group, single-centre study, consisting of a baseline screening visit, 7-day treatment period and post-study examination visit.
Subjects and intervention: 36 healthy elderly subjects (aged > or =65 years) with a body mass index of 18.5-29.9 kg/m(2). Subjects were randomized to receive dabigatran etexilate either with or without coadministration of pantoprazole. Dabigatran etexilate was administered as capsules at 150 mg twice daily over 6 days and once on the morning of day 7. Pantoprazole was administered at 40 mg twice daily, starting 2 days prior to dabigatran etexilate administration and ending on the morning of day 7.
Main outcome measures: The primary pharmacokinetic measurements included the area under the plasma concentration-time curve at steady state (AUC(ss)), maximum (C(max,ss)) and minimum (C(min,ss)) plasma concentrations at steady state, terminal half-life (t((1/2))), time to reach C(max,ss) and renal clearance of dabigatran. The secondary pharmacokinetic parameters included the mean residence time, total oral clearance and volume of distribution. The pharmacodynamic parameters measured were the blood coagulation parameters ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT).
Results: With twice-daily administration of dabigatran etexilate, plasma concentrations of dabigatran reached steady state within 2-3 days, which is consistent with a t((1/2)) of 12-14 hours. The mean (SD) peak plasma concentrations on day 4 of treatment in male and female elderly subjects were 256 ng/mL (21.8) and 255 ng/mL (84.0), respectively. The peak plasma concentrations were reached after a median of 3 hours (range 2.0-4.0 hours). Coadministration with pantoprazole decreased the average bioavailability of dabigatran (the AUC(ss)) by 24% (day 4; 90% CI 7.4, 37.8) and 20% (day 7; 90% CI 5.2, 33.3). Intra- and interindividual pharmacokinetic variability in the overall population was low (<30% coefficient of variation), indicating that dabigatran has a predictable pharmacokinetic profile. Prolongation of the ECT and aPTT correlated with, and paralleled, the plasma concentration-time profile of dabigatran, which demonstrates a rapid onset of action without a time delay, and also illustrates the direct mode of action of the drug on thrombin in plasma. The ECT increased in direct proportion to the plasma concentration, and the aPTT displayed a linear relationship with the square root of the plasma concentration. The mean AUC(ss) was 3-19% higher in female subjects than in male subjects, which was likely due to gender differences in creatinine clearance. The safety profile of dabigatran was good, with and without pantoprazole coadministration.
Conclusions: 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.