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Microdosed Cocktail of Three Oral Factor Xa Inhibitors to Evaluate Drug–Drug Interactions with Potential Perpetrator Drugs

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Abstract

Objectives

The aim of this study was to prove the suitability of simultaneously administered microdoses of the factor Xa inhibitors (FXaIs) rivaroxaban, apixaban and edoxaban (100 µg in total). To evaluate drug–drug interactions, the impact of ketoconazole, a known strong inhibitor of cytochrome P450 3A4 and P-glycoprotein, was studied.

Methods

In a crossover clinical trial, 18 healthy volunteers were randomized to the two treatments using microdoses of rivaroxaban, apixaban and edoxaban alone and when coadministered with ketoconazole. Plasma and urine concentrations of microdosed apixaban, edoxaban and rivaroxaban were quantified using a validated ultra-performance liquid chromatography–tandem mass spectrometry assay with a lower limit of quantification of 2.5 pg/ml.

Results

The microdosed FXaI cocktail showed similar pharmacokinetic parameters compared with published data, using normal therapeutic doses of each FXaI. Ketoconazole significantly increased exposure, with geometric mean AUC ratios of 1.90 (apixaban), 2.35 (edoxaban) and 2.27 (rivaroxaban).

Conclusion

The microdosed FXaI cocktail approach was able to precisely predict the drug interaction with ketoconazole. This is the first study that has been conducted to evaluate drug–drug interactions with a drug class, and the low administered doses also allow evaluation in vulnerable target populations.

Study Protocol

EudraCT 2016-003024-23.

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Acknowledgements

The authors would like to thank Sarah Mächler and Anette Lampert for monitoring the study, Marlies Stützle-Schnetz for her excellent assistance during the study performance, and Magdalena Longo and Andrea Deschlmayr for supporting the analysis of the samples.

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Authors and Affiliations

  1. Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Gerd Mikus, Kathrin I. Foerster, Marlene Schaumaeker, Marie-Louise Lehmann, Jürgen Burhenne & Walter E. Haefeli

Authors
  1. Gerd Mikus
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  2. Kathrin I. Foerster
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  3. Marlene Schaumaeker
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  4. Marie-Louise Lehmann
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  5. Jürgen Burhenne
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  6. Walter E. Haefeli
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Corresponding author

Correspondence to Gerd Mikus.

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Funding

This study was supported in part by PharmCompNet Baden Württemberg (Ministerium für Wissenschaft, Forschung und Kunst, Baden-Württemberg).

Conflict of Interest

Walter Haefeli has received speaker fees from Pfizer and Daiichi-Sankyo, and research funding from Bayer, BMS and Daiichi-Sankyo. Gerd Mikus, Kathrin Foerster, Marlene Schaumaeker, Marie-Louise Lehmann and Jürgen Burhenne declare that they have no potential conflicts of interest that might be relevant to this work.

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Mikus, G., Foerster, K.I., Schaumaeker, M. et al. Microdosed Cocktail of Three Oral Factor Xa Inhibitors to Evaluate Drug–Drug Interactions with Potential Perpetrator Drugs. Clin Pharmacokinet 58, 1155–1163 (2019). https://doi.org/10.1007/s40262-019-00749-1

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