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Results From Phase I Studies Investigating the Dose Linearity of Finerenone Tablets and the Influence of Food or pH-Modifying Comedications on its Pharmacokinetics in Healthy Male Volunteers

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that reduces the risk of adverse kidney and cardiovascular outcomes in patients with chronic kidney disease associated with type 2 diabetes mellitus. Clinical phase I studies with finerenone were carried out to assess its pharmacokinetics and the influence of common covariables on its absorption after oral administration.

Methods

Three crossover studies in healthy male volunteers with single-dose administration of finerenone investigated the dose linearity of a film-coated tablet (1.25–10 mg [n = 24] and 10–20 mg [n = 18]), the effect of food on the 20 mg tablet (n = 18), and the effects of the proton-pump inhibitor omeprazole (4 days pre-treatment and co-administration 2 h before finerenone) and an aluminum/magnesium hydroxide-containing antacid (10 mL [Maalox®] 70 mVal, simultaneous intake) on the 10 mg tablet (n = 10 and n = 11, respectively).

Results

Finerenone was rapidly absorbed (time to reach maximum plasma concentration [tmax] was 0.50–0.75 h). Area under the curve from zero to infinity (AUC∞) and the maximum concentration (Cmax) increased in proportion to dose in the range investigated in clinical phase II and phase III studies (1.25–20 mg), with point estimates for the ratio of dose-normalized AUC∞ and Cmax (20 mg/10 mg, approved therapeutic doses) of 0.9943 and 0.9301. After the administration of finerenone 20 mg with a high-fat, high-calorie meal, AUC∞ increased (+ 21%), Cmax decreased (−19%), and tmax was prolonged (2.47 vs. 0.75 h) when compared with the fasting state. Omeprazole had no effect on finerenone AUC∞ and Cmax. Maalox had no effect on finerenone AUC∞ and led to a non-clinically-relevant decrease in Cmax (−19%).

Conclusions

The pharmacokinetics of the finerenone film-coated tablet were linear. High-fat, high-calorie food had no clinically relevant effect on the pharmacokinetics of finerenone. In addition, pH-modifying comedications were not found to alter the pharmacokinetics of finerenone and were deemed safe for co-administration.

Plain Language Summary

Finerenone is a drug that is used to reduce the risk of adverse kidney and cardiovascular outcomes in patients with chronic kidney disease associated with type 2 diabetes and is licensed for use in several countries worldwide. Previous clinical trials analyzed the absorption of finerenone and how finerenone is distributed in, and eliminated from, the body (plasma concentrations) in healthy individuals. The present studies aimed to assess the absorption of finerenone by comparing dosages that are used in the real world to treat patients. In addition, different factors that would impact the absorption and plasma concentrations of finerenone (referred to as the pharmacokinetics of finerenone), including the presence of food and drugs that affect stomach acid levels, were investigated. Researchers found that the plasma concentrations of finerenone increase in proportion to the dose levels. A high-fat, high-calorie meal reduced the rate of finerenone absorption but did not have a significant impact on the amount of drug absorbed, and it can therefore be taken with or without food. When investigating finerenone administered in combination with drugs affecting stomach acid levels, researchers found that these drugs do not impact its pharmacokinetics and can be taken safely with finerenone.

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Acknowledgments

The authors and study sponsor are indebted to the healthy volunteers and their families, as well as the investigators and sites participating in the studies.

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Authors and Affiliations

  1. Bayer AG, Research & Development, Pharmaceuticals, Translational Medicine, 42096, Wuppertal, Germany

    Roland Heinig & Johannes Nagelschmitz

  2. Chrestos Concept GmbH & Co. KG, Essen, Germany

    Stephanie Loewen

Authors
  1. Roland Heinig
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  2. Johannes Nagelschmitz
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  3. Stephanie Loewen
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Corresponding author

Correspondence to Roland Heinig.

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Funding

This work was funded by Bayer AG, Wuppertal, Germany. Editorial support, including fact checking, referencing, figure preparation, formatting, proofreading, and submission was provided by Evangelia Giannakouri, PhD, and Ian Norton, PhD, of Scion, London, UK, supported by Bayer AG, Wuppertal, Germany, according to Good Publication Practice guidelines.

Conflicts of interest

RH 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 and JN have stock in Bayer AG, but are not paid in stock or stock options.

Ethics approval

All procedures in this study were in accordance with the 1964 Declaration of Helsinki (and its amendments). This article does not contain any studies with animals performed by any of the authors. All study protocols were reviewed and approved by the ethics committee of the respective medical council (Düsseldorf [studies 1 and 3] and Berlin [study 2], Germany) and by the Bundesinstitut für Arzneimittel und Medizinprodukte (The Federal Institute for Drugs and Medical Devices), Bonn, Germany.

Consent to participate

Informed consent was obtained from all individual participants included in the studies before study commencement.

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Not applicable.

Availability of data and materials

Availability of the data underlying this publication will be determined later according to Bayer’s commitment to the EFPIA/PhRMA principles for responsible clinical trial data sharing. This pertains to scope, time point and process of data access. As such, Bayer commits to sharing, upon request from qualified scientific and medical researchers, participant-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in participants for medicines and indications approved in the United States (US) and European Union (EU) as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 1, 2014. Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized participant-level data and supporting documents from clinical studies to conduct further research that can help advance medical science or improve patient care. Information on the Bayer criteria for listing studies and other relevant information is provided in the study sponsor’s section of the portal. Data access will be granted to anonymized participant-level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in the decisions made by the independent review panel. Bayer will take all necessary measures to ensure that participant privacy is safeguarded.

Code availability

Not applicable.

Authors’ contributions

RH, JN, and SL participated in the study concept and design and were involved in the acquisition, analysis, and interpretation of the respective data. All authors participated in preparing and approving the manuscript.

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Heinig, R., Nagelschmitz, J. & Loewen, S. Results From Phase I Studies Investigating the Dose Linearity of Finerenone Tablets and the Influence of Food or pH-Modifying Comedications on its Pharmacokinetics in Healthy Male Volunteers. Eur J Drug Metab Pharmacokinet 47, 549–559 (2022). https://doi.org/10.1007/s13318-022-00770-z

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