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Investigation of combined CYP3A4 inductive/inhibitory properties by studying statin interactions: a model study with the renin inhibitor ACT-178882

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Abstract

Purpose

ACT-178882, a direct renin inhibitor, was used as a model compound in an elaborate drug–drug interaction study with atorvastatin and simvastatin to explore complex CYP3A4 inductive and inhibitory properties.

Methods

Thirty-two healthy male subjects received single doses of 20 mg atorvastatin and 20 mg simvastatin on days 1, 9, 31, and 41. On days 6 to 33, 500 mg ACT-178882 was administered once daily. Plasma concentrations of ACT-178882, simvastatin, and atorvastatin were measured by LC-MS/MS. Routine safety assessments were performed throughout the study.

Results

Exposure (as based on area under the curve) to simvastatin and 6β-hydroxyacid simvastatin increased (90 % confidence interval) 4.63-fold (3.90, 5.50) and 3.71-fold (3.19, 4.32), respectively, when comparing day 9 and day 1. On day 9, exposure to atorvastatin was similar but Cmax decreased, while both variables decreased for ortho-hydroxy atorvastatin when compared to day 1. On day 31, after prolonged administration of ACT-178882, exposure to atorvastatin, ortho-hydroxy atorvastatin, simvastatin, and 6β-hydroxyacid simvastatin decreased by 14, 19, 21, and 27 %, respectively, when compared to day 9. However, on this day, exposure to simvastatin and its metabolite was still markedly higher when compared to day 1. Effects of ACT-178882 had largely dissipated on day 41.

Conclusions

This design enabled the study of complex time-dependent effects on CYP3A4 activity with clinically relevant substrates.

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Acknowledgments

The clinical part of the study was conducted at the Drug Research Unit Ghent, Ghent, Belgium with Dr. Luc Van Bortel as principal investigator. Bioanalysis of ACT-178882 was performed by Ilka Molitor at Swiss BioAnalytics, Birsfelden, Switzerland. Dr. Wolfgang Martin at Pharmakin, Ulm, Germany was responsible for the bioanalysis of simvastatin and atorvastatin and their metabolites. Editorial assistance for the preparation of the manuscript was provided by Dr. Paul van Giersbergen (Van Giersbergen Consulting, Wuenheim, France).

Contributions of authors statement

Jasper Dingemanse and Laurent B Nicolas, both Actelion Pharmaceuticals Ltd employees, designed the study, evaluated the results, and wrote the text of the manuscript. Luc van Bortel was the principal investigator of the study.

Conflict of interests

This study was sponsored by Actelion Pharmaceuticals Ltd., and Jasper Dingemanse and Laurent Nicolas are full-time employees of Actelion Pharmaceuticals Ltd Luc van Bortel is a full-time employee of the Drug Research Unit Ghent.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland

    Jasper Dingemanse & Laurent B. Nicolas

  2. Drug Research Unit Ghent, Ghent University Hospital, Ghent, Belgium

    Luc van Bortel

Authors
  1. Jasper Dingemanse
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  2. Laurent B. Nicolas
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  3. Luc van Bortel
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Corresponding author

Correspondence to Jasper Dingemanse.

Additional information

Clinical trial registry: EudraCT 2008-004710-27

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Dingemanse, J., Nicolas, L.B. & van Bortel, L. Investigation of combined CYP3A4 inductive/inhibitory properties by studying statin interactions: a model study with the renin inhibitor ACT-178882. Eur J Clin Pharmacol 70, 675–684 (2014). https://doi.org/10.1007/s00228-014-1674-1

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  • DOI: https://doi.org/10.1007/s00228-014-1674-1

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