[Rivaroxaban: clinical pharmacology].
Rivaroxaban (Xarelto) is a new oral, direct and selective inhibitor of the factor Xa of the coagulation cascade. The main pharmacokinetic characteristics of rivaroxaban are a bioavailability of approximately 80-100%, a maximum concentration obtained in 2 to 4 hours, a terminal half-life of elimination of 7 to 11 hours, a renal elimination for 1/3 for the active hepatic metabolism from the cytochrome P450 (3A4) for the other 2/3. The main sources of variability are the renal and the liver function and potential interactions with some strong inhibitors or inducers of the CYP450 3A4. Phase II clinical studies have shown that this compound can be orally administrated, once or twice daily, without any biological monitoring and without any need for dose adjustment. There is a contra-indication in case of severe liver insufficiency and not recommended in case of severe renal impairment. Pharmacodynamically, Rivaroxaban is a direct and selective factor Xa inhibitor without any effect on the factor IIa and without any interaction on platelets. Four phases II with 2787 patients were carried out to for venous thromboembolic (VTE) prophylaxis after major orthopaedic surgery, showing that 10 mg once daily could be the optimal dose regimen to assess in phase III. Two phases II with 1446 patients were carried out for the treatment of VTE showing that 15 mg twice daily for 3 weeks and then 20 mg once daily could be the optimal dose regimen to evaluate in the following phases 3. No strong signal for a potential liver toxicity was shown during these 6 phases II.
Mismetti
P
P
Groupe de Recherche sur la Thrombose, EA 3065 - CIE3, Unité de Recherche Clinique, de l'innovation et de Pharmacologie, CHU de Saint-Etienne, Université Jean Monnet, 42055 Saint-Etienne, France. mismetti@univ-st-etienne.fr
Laporte
S
S
D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001682:Biological Availability; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D000075202:Contraindications; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015394:Molecular Structure; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019637:Orthopedic Procedures; D011183:Postoperative Complications / Q000517:prevention & control; D011229:Preanesthetic Medication; D000069552:Rivaroxaban; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020246:Venous Thrombosis / Q000517:prevention & control
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human