Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement

J Clin Pharmacol. 2005 May;45(5):555-63. doi: 10.1177/0091270005274550.

Abstract

Dabigatran etexilate is an oral low-molecular-weight direct thrombin inhibitor. Following oral administration, dabigatran etexilate is rapidly converted to its active form, dabigatran. The authors investigated the absorption, distribution, and elimination of a single 150-mg dose capsule formulation of dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. In an open-label, 3-way crossover study, dabigatran etexilate was administered to 18 male volunteers in the fasted state, after administration of food and with coadministration of the proton pump inhibitor, pantoprazole. In a subsequent multicenter, open-label study, 59 patients received a single dose of dabigatran etexilate, administered 1 to 3 hours following total hip replacement. In healthy volunteers, food had no effect on the extent of absorption of dabigatran etexilate, although there was reduced interindividual variability for dabigatran maximum plasma concentration and AUC(0-infinity). A decrease in the mean dabigatran AUC(0-infinity) (904 to 705 ng*h/mL) occurred with coadministration of pantoprazole. In patients undergoing total hip replacement, immediate onset of absorption was seen with the maximum plasma concentration of dabigatran occurring after 6 hours. The AUC(0-24) of dabigatran was 88% of the steady-state AUC using a preliminary tablet formulation and 106% of that seen in the healthy volunteer study. Compared with healthy volunteers, the postoperative profile was flattened with delayed peak concentrations. In summary, administration of the dabigatran etexilate capsule with food has no effect on the extent of dabigatran absorption, with a moderate decrease when coadministered with pantoprazole. Adequate plasma concentrations of dabigatran were seen with early postoperative administration of the dabigatran etexilate capsule. These pharmacokinetic characteristics confirm the suitability of this oral solid dosage form for use in future clinical trials.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Pyridinylmethylsulfinylbenzimidazoles
  • Absorption
  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Area Under Curve
  • Arthroplasty, Replacement, Hip*
  • Benzimidazoles / pharmacokinetics*
  • Benzimidazoles / pharmacology
  • Cross-Over Studies
  • Dabigatran
  • Drug Interactions
  • Female
  • Food-Drug Interactions
  • Humans
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Omeprazole / analogs & derivatives*
  • Omeprazole / pharmacology
  • Pantoprazole
  • Proton Pump Inhibitors
  • Pyridines / pharmacokinetics*
  • Sulfoxides / pharmacology
  • Thrombin / antagonists & inhibitors*

Substances

  • 2-Pyridinylmethylsulfinylbenzimidazoles
  • Benzimidazoles
  • Proton Pump Inhibitors
  • Pyridines
  • Sulfoxides
  • Pantoprazole
  • Thrombin
  • Dabigatran
  • Omeprazole