Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa

• Published in: American journal of cardiovascular drugs : drugs, devices, and other interventions Vol. 16; no. 2; pp. 119 - 127
• Main Authors: Vakkalagadda, Blisse, Frost, Charles, Byon, Wonkyung, Boyd, Rebecca A., Wang, Jessie, Zhang, Donglu, Yu, Zhigang, Dias, Clapton, Shenker, Andrew, LaCreta, Frank
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.04.2016; Springer Nature B.V
• Subjects: Administration, Intravenous; Administration, Oral; Adult; Area Under Curve; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Cardiology; Cross-Over Studies; Cytochrome P-450 CYP3A - metabolism; Drug Interactions; Factor Xa Inhibitors - pharmacokinetics; Female; Humans; Male; Medicine; Medicine & Public Health; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy; Pyrazoles - pharmacokinetics; Pyridones - pharmacokinetics; Rifampin - administration & dosage; Young Adult; Absolute Oral Bioavailability; Single Ascend Dose Study; Rifampin; Apixaban; Breast Cancer Resistance Protein
• ISSN: 1175-3277; 1179-187X
• DOI: 10.1007/s40256-015-0157-9

Objective Apixaban is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. The effects of rifampin, a strong inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics of oral and intravenous apixaban were evaluated in an open-label, randomized, sequential crossover study. Methods Twenty healthy participants received single doses of apixaban 5 mg intravenously on day 1 and 10 mg orally on day 3, followed by rifampin 600 mg once daily on days 5–15. Finally, participants received single doses of apixaban 5 mg intravenously and 10 mg orally separately on days 12 and 14 in one of two randomized sequences. Results Apixaban, given intravenously and orally, was safe and well tolerated when administered in the presence and absence of rifampin. Apixaban absolute oral bioavailability was 49 % when administered alone and 39 % following induction by rifampin. Rifampin reduced apixaban area under the plasma concentration–time curve from time zero to infinity (AUC ∞ ) by 39 % after intravenous administration and by 54 % after oral administration. Rifampin induction increased mean clearance by 1.6-fold for intravenous apixaban and mean apparent clearance by 2.1-fold for oral apixaban, indicating rifampin affected both pre-systemic and systemic apixaban elimination pathways. Conclusion Co-administration of apixaban with rifampin reduced apixaban exposure via both decreased bioavailability and increased systemic clearance.