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Pharmacokinetics of the Novel, Selective, Non-steroidal Mineralocorticoid Receptor Antagonist Finerenone in Healthy Volunteers: Results from an Absolute Bioavailability Study and Drug–Drug Interaction Studies In Vitro and In Vivo

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Abstract

Background and Objectives

Finerenone is a selective, non-steroidal mineralocorticoid receptor antagonist. In vivo and in vitro studies were performed to assess absolute bioavailability of finerenone, the effect of metabolic enzyme inhibitors on the pharmacokinetics of finerenone and its metabolites, the quantitative contribution of the involved enzymes cytochrome P450 (CYP) 3A4 and CYP2C8 and the relevance of gut wall versus liver metabolism.

Methods

The pharmacokinetics, safety and tolerability of finerenone (1.25–10 mg orally or 0.25–1.0 mg intravenously) were evaluated in healthy male volunteers in four crossover studies. Absolute bioavailability was assessed in volunteers receiving finerenone orally and by intravenous infusion (n = 15) and the effects of erythromycin (n = 15), verapamil (n = 13) and gemfibrozil (n = 16) on finerenone pharmacokinetics were investigated. Finerenone was also incubated with cryopreserved human hepatocytes in vitro in the presence of erythromycin, verapamil or gemfibrozil.

Results

Finerenone absolute bioavailability was 43.5% due to first-pass metabolism in the gut wall and liver. The geometric mean AUC0–∞ ratios of finerenone (drug + inhibitor/drug alone) were 3.48, 2.70 and 1.10 with erythromycin, verapamil and gemfibrozil, respectively. The contribution ratio of CYP3A4 to the metabolic clearance of finerenone derived from these values was 0.88–0.89 and was consistent with estimations based on in vitro data, with the remaining metabolic clearance due to CYP2C8 involvement.

Conclusion

Finerenone is predominantly metabolized by CYP3A4 in the gut wall and liver. Increases in systemic exposure upon concomitant administration of inhibitors of this isoenzyme are predictable and consistent with in vitro data. Inhibition of CYP2C8, the second involved metabolic enzyme, has no relevant effect on finerenone in vivo.

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Acknowledgements

The authors would like to acknowledge the investigators responsible for the different studies: Dr. Michael Leidig (CRS Mönchengladbach) for his key role in the absolute bioavailability study, Dr. Angela Kentrat (ClinPharmCologne), Manuela Casjens (CRS Berlin) and Dr. Sybille Baumann (CRS Mannheim) for their valuable contributions to the drug–drug interaction in vivo studies with erythromycin, verapamil and gemfibrozil, respectively. Dr. Gabriele Rohde of Bayer AG (Wuppertal, Germany) was responsible for bioanalyses. Medical writing assistance, funded by Bayer AG, was provided by Dr. Nicolas Bertheleme of Oxford PharmaGenesis, Oxford, UK.

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Authors and Affiliations

  1. Bayer AG, Research and Development, Pharmaceuticals, Clinical Sciences, Wuppertal, Germany

    Roland Heinig & Johannes Nagelschmitz

  2. Bayer AG, Research and Development, Pharmaceuticals, DMPK, Wuppertal, Germany

    Michael Gerisch & Anna Engelen

  3. CHRESTOS Concept GmbH, & Co. KG, Essen, Germany

    Stephanie Loewen

Authors
  1. Roland Heinig
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  2. Michael Gerisch
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  3. Anna Engelen
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  4. Johannes Nagelschmitz
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  5. Stephanie Loewen
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Corresponding author

Correspondence to Roland Heinig.

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Funding

Research was funded by the sponsor, Bayer AG. Bayer AG agreed to the publication of the present data.

Conflict of interest

RH, MG, AE and JN are employees of Bayer AG. SL is an employee of Chrestos Concept GmbH & Co. KG, which received funding for this analysis from Bayer AG. In addition, RH, MG, AE and JN have stock in Bayer AG, but are not paid in stock or stock options.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed Consent

Informed consent was obtained from all participants before study commencement.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Heinig, R., Gerisch, M., Engelen, A. et al. Pharmacokinetics of the Novel, Selective, Non-steroidal Mineralocorticoid Receptor Antagonist Finerenone in Healthy Volunteers: Results from an Absolute Bioavailability Study and Drug–Drug Interaction Studies In Vitro and In Vivo. Eur J Drug Metab Pharmacokinet 43, 715–727 (2018). https://doi.org/10.1007/s13318-018-0483-9

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  • DOI: https://doi.org/10.1007/s13318-018-0483-9

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