Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa
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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.
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.
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.
Co-administration of apixaban with rifampin reduced apixaban exposure via both decreased bioavailability and increased systemic clearance.
KeywordsRifampin Apixaban Breast Cancer Resistance Protein Absolute Oral Bioavailability Single Ascend Dose Study
The authors would like to thank Suzette Girgis, Sunil Nepal, Alan Schuster and Tong Li for their contributions to this study. Editorial assistance was provided by Dana Fox, PhD, CMPP (Caudex, New York, NY, USA), and was funded by Bristol-Myers Squibb Company and Pfizer Inc.
Compliance with Ethical standards
Conflicts of interest
This study was sponsored by Bristol-Myers Squibb and Pfizer Inc. Blisse Vakkalagadda, Charles Frost, Jessie Wang, Donglu Zhang, Zhigang Yu, Clapton Dias, Andrew Shenker, and Frank LaCreta were all employees of Bristol-Myers Squibb Company at the time of research and received salaries and benefits commensurate with employment; Wonkyung Byon and Rebecca A. Boyd are employees of Pfizer Inc and received salaries and benefits commensurate with employment. All authors have full control of all primary data, and they agree to allow the journal to review their data if requested.
This study was performed at a single clinical center in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The study protocol was approved by the New England Institutional Review Board (Wellesley, Massachusetts, USA). All participants provided written, informed consent.
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