Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate

Clin Pharmacokinet. 2008;47(5):285-95. doi: 10.2165/00003088-200847050-00001.

Abstract

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.

Publication types

  • Review

MeSH terms

  • 2-Pyridinylmethylsulfinylbenzimidazoles / pharmacology
  • Animals
  • Anti-Ulcer Agents / pharmacology
  • Anticoagulants / pharmacokinetics*
  • Anticoagulants / pharmacology*
  • Benzimidazoles / pharmacokinetics*
  • Benzimidazoles / pharmacology*
  • Biological Availability
  • Dabigatran
  • Drug Interactions
  • Food-Drug Interactions
  • Humans
  • Liver Diseases / metabolism
  • Pantoprazole
  • Prodrugs / pharmacokinetics*
  • Prodrugs / pharmacology*
  • Pyridines / pharmacokinetics*
  • Pyridines / pharmacology*
  • Thrombin / antagonists & inhibitors*

Substances

  • 2-Pyridinylmethylsulfinylbenzimidazoles
  • Anti-Ulcer Agents
  • Anticoagulants
  • Benzimidazoles
  • Prodrugs
  • Pyridines
  • Pantoprazole
  • Thrombin
  • Dabigatran