Co‐administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects

• Published in: British journal of clinical pharmacology Vol. 76; no. 3; pp. 455 - 466
• Main Authors: Mueck, Wolfgang, Kubitza, Dagmar, Becka, Michael
• Format: Journal Article
• Language: English
• Published: England Blackwell Science Inc 01.09.2013
• Subjects: Adolescent; Adult; Anticoagulants - administration & dosage; Anticoagulants - pharmacokinetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Clarithromycin - administration & dosage; Clarithromycin - pharmacokinetics; Clarithromycin - pharmacology; Cytochrome P-450 CYP3A - administration & dosage; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450; Drug Interactions; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Erythromycin - administration & dosage; Erythromycin - pharmacokinetics; Erythromycin - pharmacology; healthy subjects; Humans; Ketoconazole - administration & dosage; Ketoconazole - pharmacokinetics; Ketoconazole - pharmacology; Metabolic Clearance Rate; Midazolam - administration & dosage; Midazolam - pharmacokinetics; Midazolam - pharmacology; Middle Aged; Morpholines - administration & dosage; Morpholines - pharmacokinetics; P‐glycoprotein; Rivaroxaban; Substrate Specificity; Thiophenes - administration & dosage; Thiophenes - pharmacokinetics; Young Adult; P-glycoprotein; rivaroxaban; drug interactions; cytochrome P450; healthy subjects
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.12075

Aims 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.