[Pharmacokinetics and pharmacodynamics of the new oral anticoagulants dabigatran and rivaroxaban].

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 hours following surgery, and a further 2 hours 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 hours. 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.

• Authors: Juan Pablo Ordovás Baines, Eduardo Climent Grana, Alejandro Jover Botella, Isabel Valero García
• Journal: Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria (Farm Hosp) 2009 May-Jun Vol. 33 Issue 3 Pg. 125-33 ISSN: 1130-6343 [Print] Spain
• Vernacular Title: Farmacocinética y farmacodinamia de los nuevos anticoagulantes orales.
• PMID: 19712596 (Publication Type: Journal Article)

Chemical References

• Anticoagulants
• Benzimidazoles
• Cytochrome P-450 CYP3A Inhibitors
• Factor Xa Inhibitors
• Morpholines
• Pyridines
• Thiophenes
• Rivaroxaban
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• Thrombin
• Dabigatran

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Anticoagulants (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Benzimidazoles (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Bile (metabolism)
• Biological Availability
• Cytochrome P-450 CYP3A (metabolism)
• Cytochrome P-450 CYP3A Inhibitors
• Dabigatran
• Dose-Response Relationship, Drug
• Drug Interactions
• Factor Xa Inhibitors
• Female
• Humans
• Inactivation, Metabolic
• Intestinal Absorption
• Kidney (metabolism)
• Male
• Middle Aged
• Morpholines (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Orthopedic Procedures
• Postoperative Complications (prevention & control)
• Pyridines (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Rivaroxaban
• Thiophenes (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Thrombin (antagonists & inhibitors)
• Venous Thromboembolism (drug therapy, prevention & control)
• Young Adult