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

Heinig, Roland; Gerisch, Michael; Engelen, Anna; Nagelschmitz, Johannes; Loewen, Stephanie

doi:10.1007/s13318-018-0483-9

Cited by 36 publications

(42 citation statements)

References 25 publications

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“…40,41 Finerenone is also characterized by a short plasma half-life (2 to 3 hours in patients with CKD) and lack of biologically active metabolites. 40,42,43 In sharp contrast, spironolactone is a prodrug with multiple metabolites that have prolonged duration of action. 44 This has been shown in a recent randomized trial, in which spironolactone (25 to 50 mg/d) was administered as add-on therapy in patients with resistant hypertension and eGFR of 25 to 45 ml/min per 1.73 m 2 for 12 weeks.…”

Section: Physicochemical and Pharmacokinetic Propertiesmentioning

confidence: 99%

Mineralocorticoid Receptor Antagonism in Chronic Kidney Disease

Georgianos

Agarwal

2021

Kidney International Reports

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The overactivation of the mineralocorticoid receptor (MR) in animal models of chronic kidney disease (CKD) increases sodium retention and hypertension and provokes inflammation and fibrosis in the kidneys, blood vessels, and the heart; these processes play an important role in the progression of cardiorenal disease. Accordingly, blockade of the MR is an attractive therapeutic intervention to retard the progression of CKD and improve cardiovascular morbidity and mortality. Finerenone is a novel, nonsteroidal MR antagonist (MRA) with a unique mode of action that is distinct from currently available steroidal MRAs. In animal models of CKD, finerenone has a more favorable benefit/risk ratio as compared with the steroidal MRAs such as spironolactone and eplerenone. In patients with type 2 diabetes and heart and/or kidney disease, phase II trials have revealed that compared with spironolactone, eplerenone, or placebo, finerenone displays benefits that exceed the risks of MR antagonism. In patients with CKD and type 2 diabetes, a large phase III trial has shown that, compared with placebo, finerenone improved kidney failure and cardiovascular outcomes. In the first part of this article, we explore the safety and efficacy of spironolactone and eplerenone in early-and late-stage CKD. In the second part, we describe the mechanism of action of finerenone and discuss the promising role of this nonsteroidal MRA as a novel therapeutic opportunity to improve clinical outcomes in patients with CKD.

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Section: Physicochemical and Pharmacokinetic Propertiesmentioning

confidence: 99%

Mineralocorticoid Receptor Antagonism in Chronic Kidney Disease

Georgianos

Agarwal

2021

Kidney International Reports

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“…However, as CYP1A1-specific metabolite M13 was not observed in human plasma or excreta, involvement of CYP1A1 in finerenone biotransformation was excluded. The quantitative contribution of CYP3A4 and CYP2C8 to finerenone clearance was investigated in detail in vitro with human hepatocytes supplemented with isoformspecific inhibitors, as well as in dedicated clinical drug-drug interaction studies with the moderate CYP3A4 inhibitors erythromycin and verapamil and the strong CYP2C8 inhibitor gemfibrozil (Heinig et al, 2018). In line with the in vitro phenotyping data, the dominant role of CYP3A4 in finerenone biotransformation was demonstrated by a calculated fraction metabolized of 0.88/0.89 for CYP3A4 from the clinical drug-drug interaction studies, and a minor contribution of CYP2C8 (fraction metabolized ;0.1).…”

Section: Biotransformation Of Finerenonementioning

confidence: 99%

Biotransformation of Finerenone, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, in Dogs, Rats, and Humans, In Vivo and In Vitro

et al. 2018

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Mass balance and biotransformation of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, were investigated in four healthy male volunteers following a single oral administration of 10 mg (78 Ci) of [C]finerenone and compared with data from studies in dogs and rats. The total recovery of the administered radioactivity was 101% in humans, 94.7% in dogs, and 95.2% in rats. In humans, radioactivity was mainly excreted renally (80%); in rats, it was primarily the biliary/fecal route (76%); and in dogs, excretion was more balanced. Finerenone was extensively metabolized in all species by oxidative biotransformation, with minor amounts of unchanged drug in excreta (humans: 1%; dogs, rats: <9%). In vitro studies suggested cytochrome P450 3A4 was the predominant enzyme involved in finerenone metabolism in humans. Primary metabolic transformation involved aromatization of the dihydronaphthyridine moiety of metabolite M1 as a major clearance pathway with a second oxidative pathway leading to M4. These were both prone to further oxidative biotransformation reactions. Naphthyridine metabolites (M1-M3) were the dominant metabolites identified in human plasma, with no on-target pharmacological activity. In dog plasma, finerenone and metabolite M2 constituted the major components; finerenone accounted almost exclusively for drug-related material in rat plasma. For metabolites M1-M3, axial chirality was observed, represented by two atropisomers (e.g., M1a and M1b). Analysis of plasma and excreta showed one atropisomer (a-series, >79%) of each metabolite predominated in all three species. In summary, the present study demonstrates that finerenone is cleared by oxidative biotransformation, mainly via naphthyridine derivatives.

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“…The clinical pharmacology program for finerenone comprises 27 phase I studies to date and the main results have been published [10][11][12][13][14][15]. The program was complemented by population pharmacokinetic (PK) and pharmacodynamic analyses including evaluations of patients in latestage studies.…”

Section: Introductionmentioning

confidence: 99%

Finerenone Dose-Exposure-Response for the Primary Kidney Outcome in FIDELIO-DKD Phase III: Population Pharmacokinetic and Time-to-Event Analysis

Berg¹,

Ruppert²,

Mesic³

et al. 2021

Clin Pharmacokinet

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Background Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist that recently demonstrated efficacy in delaying chronic kidney disease progression and reducing cardiovascular events in patients with chronic kidney disease and type 2 diabetes in FIDELIO-DKD, where 5734 patients were randomized 1:1 to receive either titrated finerenone doses of 10 or 20 mg once daily or placebo, with a median follow-up of 2.6 years. Methods Nonlinear mixed-effects population pharmacokinetic models were used to analyze the pharmacokinetics in FIDELIO-DKD, sparsely sampled in all subjects receiving finerenone. Post-hoc model parameter estimates together with dosing histories allowed the computation of individual exposures used in subsequent parametric time-to-event analyses of the primary kidney outcome. Results The population pharmacokinetic model adequately captured the typical pharmacokinetics of finerenone and its variability. Either covariate effects or multivariate forward-simulations in subgroups of interest were contained within the equivalence range of 80–125% around typical exposure. The exposure-response relationship was characterized by a maximum effect model estimating a low half-maximal effect concentration at 0.166 µg/L and a maximal hazard decrease at 36.1%. Prognostic factors for the treatment-independent chronic kidney disease progression risk included a low estimated glomerular filtration rate and a high urine-to-creatinine ratio increasing the risk, while concomitant sodium-glucose transport protein 2 inhibitor use decreased the risk. Importantly, no sodium-glucose transport protein 2 inhibitor co-medication-related modification of the finerenone treatment effect per se could be identified. Conclusions None of the tested pharmacokinetic covariates had clinical relevance in FIDELIO-DKD. Finerenone effects on kidney outcomes approached saturation towards 20 mg once daily and sodium-glucose transport protein 2 inhibitor use provided additive benefits. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-021-01082-2.

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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

Cited by 36 publications

References 25 publications

Mineralocorticoid Receptor Antagonism in Chronic Kidney Disease

Mineralocorticoid Receptor Antagonism in Chronic Kidney Disease

Biotransformation of Finerenone, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, in Dogs, Rats, and Humans, In Vivo and In Vitro

Finerenone Dose-Exposure-Response for the Primary Kidney Outcome in FIDELIO-DKD Phase III: Population Pharmacokinetic and Time-to-Event Analysis

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