Pharmacokinetics and Pharmacodynamics of the Direct Oral Thrombin Inhibitor Dabigatran in Healthy Elderly Subjects
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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 ≥65 years) with a body mass index of 18.5–29.9 kg/m2. 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 (AUCss), maximum (Cmax,ss) and minimum (Cmin,ss) plasma concentrations at steady state, terminal half-life (t½), time to reach Cmax,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).
With twice-daily administration of dabigatran etexilate, plasma concentrations of dabigatran reached steady state within 2–3 days, which is consistent with a t½ 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 AUCss) 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 AUCss 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.
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.
KeywordsDabigatran Interindividual Variability Pantoprazole Fondaparinux Dabigatran Etexilate
This study was funded by Boehringer Ingelheim Pharma GmbH & Co. KG (Biberach, Germany). Dr Stangier (drug metabolism and pharmacokinetics) Mrs Stähle (medical data services) and Dr Rathgen (clinical research) are employees of Boehringer Ingelheim. Dr Fuhr (study investigator) is an employee of PAREXEL International GmbH (Berlin, Germany). The authors have no other conflicts of interest that are directly relevant to the content of this study.
- 8.Wienen W, Nar H, Ries UJ, et al. 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 no. P761]. Thromb Haemost 2001; 85: 216Google Scholar
- 9.Wienen W, Nar H, Ries UJ, et al. 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 no. OC853]. Thromb Haemost 2001; 86: 232Google Scholar
- 12.Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. Epub 2007 Nov 15Google Scholar
- 21.Stangier J, Rathgen K, Stähle H, et al. Coadministration of the oral direct thrombin inhibitor dabigatran etexilate and diclofenac has little impact on the pharmacokinetics of either drug [poster no. P-T-677]. XXIst Congress of the International Society on Thrombosis and Haemostasis; 2007 Jul 6–12; GenevaGoogle Scholar
- 22.Stangier J, Stähle H, Rathgen K, et al. Coadminstration of the oral direct thrombin inhibitor dabigatran etexilate and atorvastatin has little impact on the pharmacokinetics and pharmacodynamics of either drug [poster no. P-W-671]. XXIst Congress of the International Society on Thrombosis and Haemostasis; 2007 Jul 6–12; GenevaGoogle Scholar
- 23.Stangier J, Stähle H, Rathgen K, et al. No interaction of the oral direct thrombin inhibitor dabigatran etexilate and digoxin [poster no. P-W-672]. XXIst Congress of the International Society on Thrombosis and Haemostasis; 2007 Jul 6–12; GenevaGoogle Scholar
- 24.Stangier J, Rathgen K, Stähle H, et al. Pharmacokinetics and pharmacodynamics of dabigatran etexilate in subjects with moderate hepatic impairment [poster no. P-W-673]. XXIst Congress of the International Society on Thrombosis and Haemostasis; 2007 Jul 6–12; GenevaGoogle Scholar
- 30.Stangier J, Bravo ML, Hettiarachchi R, et al. Pharmacokinetics and pharmacodynamics of dabigatran in patients undergoing total hip or knee replacement in BISTRO-2 [abstract/poster no. FP40]. 18th International Congress on Thrombosis; 2004 Jun 20–24; Ljubljana, Slovenia. Pathophysiol Haemost Thromb 2003; 33 Suppl. 2: XIVGoogle Scholar