The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects.
OBJECTIVE
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 (V(z)/F) of 1860 l (range 1430-2400 l) and the apparent total clearance after oral administration (CL(tot)/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.
Stangier
Joachim
J
Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.
Rathgen
Karin
K
Stähle
Hildegard
H
Gansser
Dietmar
D
Roth
Willy
W
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001562:Benzimidazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001780:Blood Coagulation Tests; D000069604:Dabigatran; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000925:Anticoagulants; D001562:Benzimidazoles; D011725:Pyridines; D000069604:Dabigatran