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

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Abstract

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.

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Acknowledgments

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.

Author information

Authors and Affiliations

  1. Research and Development, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Mail Stop E12-16, Route 206 and Province Line Road, Princeton, NJ, 08543-4000, USA

    Blisse Vakkalagadda, Charles Frost, Zhigang Yu, Clapton Dias, Andrew Shenker & Frank LaCreta

  2. Global Innovative Pharma Business Clinical Pharmacology, Pfizer Inc, Groton, CT, USA

    Wonkyung Byon & Rebecca A. Boyd

  3. Global Biometric Sciences, Bristol-Myers Squibb Company, Princeton, NJ, USA

    Jessie Wang

  4. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, NJ, USA

    Donglu Zhang

Authors
  1. Blisse Vakkalagadda
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  2. Charles Frost
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Corresponding author

Correspondence to Charles Frost.

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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.

Ethical standards

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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Vakkalagadda, B., Frost, C., Byon, W. et al. Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa. Am J Cardiovasc Drugs 16, 119–127 (2016). https://doi.org/10.1007/s40256-015-0157-9

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  • DOI: https://doi.org/10.1007/s40256-015-0157-9

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