title: Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects.
abstract: OBJECTIVE
  The anticoagulant rivaroxaban is an oral, direct Factor Xa inhibitor for the management of thromboembolic disorders. Metabolism and excretion involve cytochrome P450 3A4 (CYP3A4) and 2J2 (CYP2J2), CYP-independent mechanisms, and P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) (ABCG2).
  
  
  METHODS
  The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P-gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers.
  
  
  RESULTS
  Rivaroxaban did not interact with midazolam (CYP3A4 probe substrate). Exposure to rivaroxaban when co-administered with midazolam was slightly decreased by 11% (95% confidence interval [CI] -28%, 7%) compared with rivaroxaban alone. The following drugs moderately affected rivaroxaban exposure, but not to a clinically relevant extent: erythromycin (moderate CYP3A4/P-gp inhibitor; 34% increase [95% CI 23%, 46%]), clarithromycin (strong CYP3A4/moderate P-gp inhibitor; 54% increase [95% CI 44%, 64%]) and fluconazole (moderate CYP3A4, possible Bcrp [ABCG2] inhibitor; 42% increase [95% CI 29%, 56%]). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4, P-gp/Bcrp (ABCG2) inhibitors (and potential CYP2J2 inhibitors) ketoconazole (158% increase [95% CI 136%, 182%] for a 400 mg once daily dose) and ritonavir (153% increase [95% CI 134%, 174%]).
  
  
  CONCLUSIONS
  Results suggest that rivaroxaban may be co-administered with CYP3A4 and/or P-gp substrates/moderate inhibitors, but not with strong combined CYP3A4, P-gp and Bcrp (ABCG2) inhibitors (mainly comprising azole-antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi-pathway inhibitors of rivaroxaban clearance and elimination.
authors.affiliation: Bayer HealthCare Pharmaceuticals, Wuppertal, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueck
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kubitza
authors.forename: Michael
authors.initials: M
authors.lastname: Becka
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017291:Clarithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000090762:Cytochrome P-450 CYP2J2; D051544:Cytochrome P-450 CYP3A / Q000008:administration & dosage / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004917:Erythromycin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000069552:Rivaroxaban; D013379:Substrate Specificity; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000925:Anticoagulants; C000717350:CYP2J2 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D009025:Morpholines; D013876:Thiophenes; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D000069552:Rivaroxaban; D000090762:Cytochrome P-450 CYP2J2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017291:Clarithromycin; D008874:Midazolam; D007654:Ketoconazole
keywords: P-glycoprotein; cytochrome P450; drug interactions; healthy subjects; rivaroxaban