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Investigation of the Mutual Pharmacokinetic Interactions Between Bosentan, a Dual Endothelin Receptor Antagonist, and Simvastatin

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Abstract

Background: In vitro, bosentan has been shown to be a mild inducer of cytochrome P450 (CYP) 2C9 and 3A4.

Purpose: To investigate in vivo the mutual pharmacokinetic interactions between bosentan and simvastatin, a CYP3A4 substrate.

Methods: Nine healthy male subjects were treated in a three-period randomised crossover study with: (A) bosentan 125mg twice daily for 5.5 days; (B) simvastatin 40mg once daily for 6 days; and (C) bosentan 125mg twice daily and simvastatin 40mg once daily for 5.5 and 6 days, respectively. Plasma concentration-time profiles of bosentan and its metabolites (treatments A and C) and simvastatin and β-hydroxyacid simvastatin (treatments B and C) were determined on day 6.

Results: Steady-state conditions for bosentan and its metabolites were attained on day 4 of treatment. The pharmacokinetic parameters of bosentan and its metabolites were not influenced by concomitant treatment with simvastatin: areas under the plasma concentration-time curve over one administration interval of 12 hours (AUCτ) [geometric mean and 95% CI] were 4586 (3719–5656) and 4928 (3945–6156) μg · h/L. In contrast, bosentan significantly reduced exposure to simvastatin and β-hydroxyacid simvastatin by 34 and 46%, respectively. AUC> values for simvastatin were 30.5 (23.1–40.2) and 20.0 (15.9–25.1) μg · h/L and for β-hydroxyacid simvastatin 43.0 (32.1–57.8) and 23.4 (16.7–32.6) μg · h/L in treatments B and C, respectively.

Conclusion: Concomitant treatment with bosentan reduces the exposure to simvastatin and β-hydroxyacid simvastatin by approximately 40%, indicating that in vivo bosentan is also a mild inducer of CYP3A4.

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Acknowledgements

Actelion Pharmaceuticals Ltd financially supported this study. The authors have provided no information on conflicts of interest directly relevant to the content of this study.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 18, 4123, Allschwil, Switzerland

    Jasper Dingemanse & Paul L. M. van Giersbergen

  2. Pharos GmbH, Ulm, Germany

    Dieter Schaarschmidt

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  1. Jasper Dingemanse
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  2. Dieter Schaarschmidt
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  3. Paul L. M. van Giersbergen
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Correspondence to Jasper Dingemanse.

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Dingemanse, J., Schaarschmidt, D. & van Giersbergen, P.L.M. Investigation of the Mutual Pharmacokinetic Interactions Between Bosentan, a Dual Endothelin Receptor Antagonist, and Simvastatin. Clin Pharmacokinet 42, 293–301 (2003). https://doi.org/10.2165/00003088-200342030-00004

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