Pharmacokinetics and pharmacodynamics of the new oral anticoagulants

Abstract

Dabigatran is the first available oral direct thrombin inhibitor anticoagulant. Absorption of the prodrug, dabigatran etexilate and its conversion to dabigatran is rapid (peak plasma concentrations are reached 4–6 h following surgery, and a further 2 h later). Its oral bioavailability is low, but shows reduced interindividual variability. Dabigatran specifically and reversibly inhibits thrombin, the key enzyme in the coagulation cascade. Studies both in healthy volunteers and in patients undergoing major orthopaedic surgery show a predictable pk/pd profile that allows for fixed-dose regimens. The anticoagulant effect correlates adequately with the plasma concentrations of the drug, demonstrating effective anticoagulation combined with a low risk of bleeding. Dabigatran is mainly eliminated by renal excretion (a fact which affects the dosage in elderly and in moderate-severe renal failure patients), and no hepatic metabolism by cytochrome P450 isoenzymes has been observed, showing a good interaction profile.

Rivaroxaban will probably be the first available oral factor Xa (FXa) direct inhibitor anticoagulant drug. It produces a reversible and predictable inhibition of FXa activity with potential to inhibit clot-bound FXa. Its pharmacokinetic characteristics include rapid absorption, high oral availability, high plasma protein binding and a half-life of aprox. 8 h. Rivaroxaban elimination is mainly renal, but also through faecal matter and by hepatic metabolism. Although the drug has demonstrated moderate potential to interact with strong CYP3A4 inhibitors, it does not inhibit or induce any major CYP450 enzyme.