Received: 6 September 2023 Revised: 14 November 2023 Accepted: 15 November 2023

DOI: 10.1111/dom.15387

ORIGINAL ARTICLE

Pharmacokinetics and pharmacodynamics of finerenone in

patients with chronic kidney disease and type 2 diabetes:
Insights based on FIGARO-DKD and FIDELIO-DKD

Thomas Eissing PhD 1† | Sebastiaan Camiel Goulooze PhD 2† |

Paul van den Berg MSc 2 | Martijn van Noort PhD 2
| Martijn Ruppert MSc 2 |
Nelleke Snelder PhD 2 | Dirk Garmann PhD 1 | Joerg Lippert PhD 1 |
Roland Heinig PhD 3 | Meike Brinker MD 4
| Hiddo J. L. Heerspink PhD 5

1
Bayer AG, Pharmaceuticals R&D,
Pharmacometrics, Leverkusen, Germany
2
Leiden Experts on Advanced
Pharmacokinetics and Pharmacodynamics
(LAP&P), Leiden, The Netherlands
3
Bayer AG, Pharmaceuticals R&D, Clinical
Pharmacology, Wuppertal, Germany
4
Bayer AG, Pharmaceuticals R&D, Clinical
Development, Wuppertal, Germany
5
Department of Clinical Pharmacy and
Pharmacology, University of Groningen,
University Medical Center Groningen,
Groningen, The Netherlands
Correspondence
Thomas Eissing, Bayer AG, Pharmaceuticals
Research & Development, Pharmacometrics,
51368, Leverkusen, Germany.
Email: thomas.eissing@bayer.com
Funding information
Bayer AG
Abstract
Aims: To perform dose–exposure–response analyses to determine the effects of
finerenone doses.
Materials and Methods: Two randomized, double-blind, placebo-controlled phase
3 trials enrolling 13 026 randomized participants with type 2 diabetes (T2D) from
global sites, each with an estimated glomerular filtration rate (eGFR) of 25 to 90 mL/
min/1.73 m2, a urine albumin-creatinine ratio (UACR) of 30 to 5000 mg/g, and serum
potassium ≤ 4.8 mmol/L were included. Interventions were titrated doses of finere-
none 10 or 20 mg versus placebo on top of standard of care. The outcomes were tra-
jectories of plasma finerenone and serum potassium concentrations, UACR, eGFR
and kidney composite outcomes, assessed using nonlinear mixed-effects population
pharmacokinetic (PK)/pharmacodynamic (PD) and parametric time-to-event models.
Results: For potassium, lower serum levels and lower rates of hyperkalaemia were asso-
ciated with higher doses of finerenone 20 mg compared to 10 mg (p < 0.001). The
PK/PD model analysis linked this observed inverse association to potassium-guided dose
titration. Simulations of a hypothetical trial with constant finerenone doses revealed a
shallow but increasing exposure–potassium response relationship. Similarly, increasing
finerenone exposures led to less than dose-proportional increasing reductions in mod-
elled UACR. Modelled UACR explained 95% of finerenone's treatment effect in slowing
chronic eGFR decline. No UACR-independent finerenone effects were identified. Nei-
ther sodium-glucose cotransporter-2 (SGLT2) inhibitor nor glucagon-like peptide-1
receptor agonist (GLP-1RA) treatment significantly modified the effects of finerenone in
reducing UACR and eGFR decline. Modelled eGFR explained 87% of finerenone's treat-
ment effect on kidney outcomes. No eGFR-independent effects were identified.

†
TE and SCG contributed equally to this work.

Trial Registration: ClinicalTrials.gov numbers NCT02540993 and NCT02545049.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2023 Bayer AG. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Diabetes Obes Metab. 2023;1–13. wileyonlinelibrary.com/journal/dom 1

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2 EISSING ET AL.

Conclusions: The analyses provide strong evidence for the effectiveness of finere-
none dose titration in controlling serum potassium elevations. UACR and eGFR are
predictive of kidney outcomes during finerenone treatment. Finerenone's kidney effi-
cacy is independent of concomitant use of SGLT2 inhibitors and GLP-1RAs.

KEYWORDS
eGFR, finerenone, hyperkalaemia, kidney outcome, serum potassium, UACR

1 | I N T RO DU CT I O N In brief, both trials were randomized, double-blind, placebo-

Finerenone recently demonstrated cardiorenal protection on top of
standard of care (SOC; optimized renin–angiotensin system [RAS] inhi-
bition) in patients with chronic kidney disease (CKD) and type 2 diabe-
tes (T2D) in the pivotal phase 3 FIDELIO-DKD and FIGARO-DKD
studies.1,2 In addition, pooled data from both studies have been ana-
lysed under the acronym FIDELITY.3,4 Based on the pharmacological
mechanism of action, hyperkalaemia is common with RAS inhibition as
well as mineralocorticoid receptor (MR) antagonism.3,5–9 As low esti-
mated glomerular filtration rate (eGFR) is an independent risk factor for
hyperkalaemia, the finerenone starting dose in the phase 3 studies was
2
10 mg for patients with eGFR <60 mL/min/1.73 m and 20 mg for
patients with eGFR ≥60 mL/min/1.73 m2. Finerenone dose titration
was guided by measurement of serum potassium and eGFR decline.1,2
In pharmacology, pharmacokinetics relate drug dose to (plasma)
exposure and pharmacodynamics describe the effects related to
exposure.10 While common in the early stages of (clinical) drug
development, a stepwise pharmacokinetic (PK)/pharmacodynamic
(PD) approach to studying efficacy and safety is also regularly applied
in late-stage development and is a cornerstone of model-informed
11–13
drug development. PK/PD analyses may provide a different per-
spective on groupwise comparisons of responses to treatment, or, by
accounting for variability due to individual dose and exposure differ-
ences, may provide more insight into between-individual variation in
drug exposure, PD response, or outcome. In studies where doses of
treatment interventions are titrated, dose–response insights are par-
ticularly challenging to obtain without explicitly considering titration
and the resultant temporal changes in dose, exposure and responses.
In this study, we investigate the relationship between finerenone
dosing and PK exposure, and then to downstream PD responses in
serum potassium, urine albumin-creatinine ratio (UACR) and eGFR, as
well as kidney outcomes, based on data from the pivotal phase 3 stud-
ies (FIGARO-DKD and FIDELIO-DKD).
2 | METHODS
2.1 | Clinical study
Details of the study design, patient characteristics and the main
results of FIDELIO-DKD and FIGARO-DKD have been previously
published, including information on informed consent, ethics and bioa-
nalytical methods.1,2,14,15
controlled phase 3 studies investigating the safety and efficacy of
finerenone in addition to SOC (maximally tolerated labelled doses of
an RAS inhibitor), on the progression of kidney disease
(FIDELIO-DKD) and the reduction of cardiovascular-related mortality
and morbidity (FIGARO-DKD) in patients with CKD and T2D. The
starting dose of the study drug in both studies was selected based on
eGFR measured at the screening visit: Patients started on finerenone
10 mg/day or matching placebo if their eGFR was between
25 and < 60 mL/min/1.73 m2, while if their eGFR was ≥60 mL/
min/1.73 m2, the starting dose was 20 mg/day. Patients could be
uptitrated and downtitrated from Month 1 onwards according to
changes in eGFR and serum potassium.
In this study, we evaluated the PK characteristics of finerenone
and their relation to serum potassium, UACR and eGFR, as well as the
kidney composite outcome composed of: (i) time to the first occur-
rence of kidney failure; (ii) a sustained decrease in eGFR ≥ 57% from
baseline over at least 4 weeks; or (iii) death from kidney causes, a sec-
ondary endpoint in both trials. The PK characteristics of finerenone
were evaluated using a sparse sampling approach in all participating
patients.16
2.2 | Model-based analyses
Stepwise PK/PD model development has been detailed previously for
FIDELIO-DKD16,17 and was conducted analogously in the present
study, thereby extending the results to a broader population including
FIGARO-DKD.
We used nonlinear mixed-effects population PK models to ana-
lyse the PK results in FIGARO-DKD, which were compared to previ-
ous results obtained for FIDELIO-DKD.16 Post hoc model parameter
estimates accompanied by dosing histories allowed the computation
of individual exposures that were used in subsequent PK/PD analyses.
Final FIGARO-DKD models for PK characteristics and serum
potassium had a similar model structure to those developed for
FIDELIO-DKD. This allowed for comparisons of model-derived param-
eter estimates, covariate effects and simulations between the two
studies. PK/PD analyses of serum potassium in FIGARO-DKD were
compared with results from FIDELIO-DKD,7 including observed serum
potassium data stratified by current dose level from both studies and
the pooled FIGARO-DKD and FIDELIO-DKD dataset. To define a
safety outcome of hyperkalaemia, we used serum potassium limits of
>5.5 and >6.0 mmol/L from the model and from the clinical data. Both

EISSING ET AL.
PK and serum potassium PD model development were prespecified
for each study and, as described for FIDELIO-DKD. The FIGARO-
DKD model development started on an interim data cut. No additional
model was developed using pooled data because the consistent
models obtained for both PK characteristics and potassium based on
the two individual studies did not suggest relevant benefits.
In subsequent additional exploratory PK/PD analyses of UACR
and eGFR, based on previous experience, no model was developed
using the FIGARO-DKD data alone. Pooled data from both studies
were directly used for model development to increase precision and
reliability in selected findings.17 While FIDELIO-DKD analyses of the
kidney outcome directly related exposure and outcome in one step,16
here we related modelled eGFR to kidney outcome, thus relating PK
to PD characteristics to outcome in a stepwise fashion.
Each analysis included model qualification steps as described
previously,7,16,17 and each figure presented in this paper includes rep-
resentative visual predictive check subfigure(s) to qualify the different
models against the respective data. All model files and final parameter
tables are provided in the supplementary material.
The proportions of finerenone's treatment effect explained by
the biomarkers UACR (for finerenone's effect on chronic eGFR
decline) and eGFR (for finerenone's effect on the composite kidney
endpoint [comprising time to the first occurrence of kidney failure, a
sustained decrease in eGFR ≥57% from baseline over at least
4 weeks, or death from kidney causes]) were calculated by comparing
the estimated treatment effect size between models with and without
18
these biomarkers as time-varying covariates.
3 | RESULTS
To better understand the influence of finerenone dosing on safety
and efficacy, we analysed dose–exposure–response relationships,
Dose titration
Sustained
Short-term
Finerenone Finerenone
PK
dose exposure Long-term
Covariates
Sustained
F I G U R E 1 Finerenone dose–exposure–response analysis scheme. As finerenone affects serum potassium and estimated glomerular filtration
rate (eGFR), which are themselves used to titrate the finerenone dose level, this introduces a ‘feedback’ loop, as further explained throughout the
manuscript. K+, serum potassium; PD, pharmacodynamics; PK, pharmacokinetics; UACR, urine albumin-creatinine ratio.
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3
as outlined in Figure 1, based on data from FIGARO-DKD and
FIDELIO-DKD. The primary results of the two phase 3 studies as
well as baseline characteristics of the study participants have been
detailed previously.1,2,14,15 Of the patients eligible for analysis in
FIGARO-DKD and FIDELIO-DKD, 3666 and 2841 were randomized
to placebo, respectively, and 3686 and 2833 to finerenone, respec-
tively.1,2 The median (5th–95th percentile) eGFR was 67.6
(33.3–103) and 43.0 (26.7–66.9) mL/min/1.73 m2, and the median
(5th–95th percentile) UACR was 308 (36.8–2115) and 852
(140–3366) mg/g, in FIGARO-DKD and FIDELIO-DKD, respec-
tively. The average dose level over time was 17.5 and 15.1 mg in
FIGARO-DKD and FIDELIO-DKD, respectively.1,2 Table S1 summa-
rizes patient characteristics that were tested as covariates in the
following analyses.
3.1 | Pharmacokinetics
We first evaluated the finerenone dose and exposure relationship
using a population PK model. The final FIGARO-DKD PK dataset con-
tained 8142 valid finerenone concentrations from 3102 patients. As
in FIDELIO-DKD,16 the PK characteristics of finerenone in
FIGARO-DKD could be described by a linear two-compartment
model, a first-order elimination from the central compartment, and
a delayed first-order absorption.
The covariates listed in Table S1 were tested and selected in a
forward inclusion and backward deletion procedure. The covariates
and their influence identified for FIGARO-DKD were comparable to
those identified for FIDELIO-DKD. Differences in maximal (Cmax) and
integral (area under the curve [AUC]) exposure for categorical covari-
ates as well as for continuous covariates at the 5th and 95th percen-
tiles of the covariate distribution were within an equivalence range of
80%–125% (around typical exposure; Figure 2A).
PD Safety
K+ Hyperkalaemia
eGFR/kidney
eGFR
function
Progression
UACR Covariates
Efficacy
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4 EISSING ET AL.

(A) 0.8 0.9 1.0 1.1 1.2 1.3 0.8 0.9 1.0 1.1 1.2 1.3
Ratio Cmax,md Ratio AUCt,md
eGFR-EPI
time-varying
Creatine

Body weight

Body surface area

Body height
Gamma glutamyl
transferase
Alkaline phosphatase

Total protein
Smoking status:
former/current
Smoking status:
never
Korean ethnicity

All other races/ethnicities

SGLT2 inhibitor:
none or 0-50%
SGLT2 inhibitor:
>50%
CYP3A4 inhibitor:
none
CYP3A4 inhibitor:
<50% or unclassified
CYP3A4 inhibitor:
>50%

FIDELIO-DKD FIGARO-DKD

(B)
Prediction corrected finerenone concentration (μg/L)

1,000.00

100.00

10.00

1.00

0.10

0 10 20 30
Time after dose (h)

Observed data CI of predicted quantile CI of predicted median Observed median Observed quantiles

(C) (D) (E)

30
Dose-normalized AUCτ,md (μg*h/L/mg)

100
Dose-normalized Cmax,md (μg/L/mg)

300
Concentration (μg/L)

50
200
10
30

100

10 3 0
0 4 8 12 16 20 24
Y

Y
KD

KD

KD

KD
IT

IT
-D

-D

-D

-D
EL

EL

Time after dose (h)

IO

IO

O
D

D
AR

AR
FI

FI
EL

EL
G

G
D

D
FI

FI
FI

FI

Study Study

FIGURE 2 Legend on next page.

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EISSING ET AL. 5

The final model adequately captured the PK characteristics of
finerenone in FIGARO-DKD (Figure 2B). The estimated AUC and Cmax
median values were 10% and 7% lower, respectively, than those esti-
mated for FIDELIO-DKD (Figure 2C,D), which enrolled patients with
more advanced disease. Simulations shown at steady state in a pooled
population from both studies illustrate the peak to trough profile
(Figure 2E), reflective of finerenone's short half-life of 2–3 h.
Body weight and eGFR were consistently identified as covariates
in current and previous analyses16,19 and appear to be the intrinsic
factors with the largest influence on finerenone exposure. Based on
additional covariates tested and included in phase 3 analyses and cor-
relations among them, the multivariate effect of these patient charac-
teristics is somewhat larger than indicated in the monovariate analysis
shown in Figure 2A. PK parameter post hoc estimates from both
phase 3 studies (individually as well as pooled) are shown in
Figure 2C,D. After stratification of the pooled post hoc estimates for
body weight, the geometric mean ratios (90% confidence interval [CI])
of patients <58.0 kg and ≥123.6 kg (5th and 95th percentiles of the
weight distribution) compared to the main category were 1.25 (1.21–
1.29) and 0.81 (0.79–0.84), respectively, for AUC and 1.42 (1.39–
1.45) and 0.71 (0.69–0.72), respectively, for Cmax. The geometric
ratios (90% CI) for patients with CKD stages 4, 3 and 2 compared to
CKD stage 1 were 1.37 (1.33–1.41), 1.27 (1.25–1.30) and 1.13 (1.10–
1.15), respectively, for AUC, and 1.27 (1.24–1.31), 1.19 (1.17–1.21)
and 1.09 (1.07–1.12), respectively, for Cmax.
The population PK analysis also provided individual exposure esti-
mates for subsequent population PK/PD models of serum potassium,
UACR and eGFR.
3.2 | Serum potassium
Dose titration implemented in both trials resulted in noncon-
stant dosing over time, which made dose–response analysis of the
longitudinal potassium data challenging. As a first-data approach,
we grouped potassium measurements based on the dose level prior
to measurement, that is, a patient's assignment to a dose group
could change over time (Figure 3A). In FIGARO-DKD, higher serum
potassium levels and frequencies of hyperkalaemia (serum potas-
sium >5.5 or >6.0 mmol/L) were observed in the active treatment
arm than in the placebo arm. However, there was an inverse correla-
tion between the serum potassium levels and the finerenone dose
level (Pearson correlation test, p < 0.001 [Figure 3A]), similar to
FIDELIO-DKD.7 Consequently, and as observed in the pooled data
of both studies (Figure 3A), the highest incidences of serum potas-
sium values >5.5 or >6.0 mmol/L were in patients in the active
treatment arm during treatment interruption or discontinuation, and
hyperkalaemia incidences on 10-mg doses were 164% or 173%,
respectively, more frequent than on 20-mg doses, reflective of
titration.
We developed a PK/PD model for serum potassium whereby the
finerenone effect on potassium was dependent on individual exposure
considering individual dosing. The tested and identified covariates are
summarized in Table S1. The visual predictive check in Figure 3B indi-
cates that the model described the data well. A clinical trial simulation
considering dose titration reproduced the observed inverse associa-
tion of potassium levels and dose (Figure 3C). Simulations for fixed
doses, that is, without titration, revealed the underlying dose–expo-
sure–response relationship, with higher doses and exposures leading
to higher potassium values (Figure 3D). The predicted median serum
potassium levels were 4.49, 4.62 and 4.68 mmol/L for placebo and
fixed finerenone doses of 10 and 20 mg, respectively.

Potassium analyses of FIGARO-DKD considered a total of 205 121
serum potassium observations (87 691 from local and 117 430 from
central laboratory) from 13 112 patients (7352 from the FIGARO-
DKD study population and 5760 from screening failures), slightly
exceeding the numbers for FIDELIO-DKD.7
3.3 | UACR and eGFR
The UACR and eGFR analyses of pooled data from FIGARO-DKD and
FIDELIO-DKD considered a total of 75 503 UACR and 186 756 eGFR
observations from 13 026 patients. Tested and identified covariates

F I G U R E 2 Finerenone pharmacokinetics in FIGARO-DKD compared to FIDELIO-DKD. (A) Forest plots illustrating the influence of the
identified covariates for FIGARO-DKD (blue) compared to FIDELIO-DKD (red). Effects on Cmax,md and AUCτ,md relative to the median covariate
value (continuous covariates) or reference subgroup (categorical covariates). Dots indicate the reference or the fold change relative to the
reference. Whiskers, shaped as an arrow, indicate the pharmacokinetic parameter values at the 5th–95th percentiles of the covariate distribution,
where the rear end of the arrow corresponds to the 5th percentile and the tip of the arrow corresponds to the 95th percentile of the covariate
distribution. Coloured bars indicate the uncertainty (5th–95th percentiles of the simulated 5th percentile, median and 95th percentile based on
10 000 simulated pharmacokinetic curves). Vertical dashed lines indicate unity and general acceptance range for equivalence of 0.8–1.25.
(B) Prediction-corrected visual predictive check on logarithmic y-axis of the FIGARO-DKD pharmacokinetic model for finerenone. Black/grey
dots: prediction-corrected observations; blue line: observed median; red dashed lines: 2.5th (as long as above the lower limit of quantification)
and 97.5th percentiles of observations; blue area: 95% variability-based prediction interval of the simulated medians; red area: 95% prediction
interval; grey triangles: observations below the lower limit of quantification. (C) Boxplots of dose-normalized AUC and (D) Cmax post hoc
parameter estimates in both studies and pool, and (E) simulation at steady state on linear y-axis for FIDELITY (green). AUCτ,md, area under the
finerenone plasma concentration-time curve within a 24 hour dosing interval at steady state after once daily dosing; CI, confidence interval;
Cmax,md, maximum finerenone plasma concentration at steady state after once daily dosing; CYP3A4, cytochrome P450 3A4; eGFR-EPI, estimated
glomerular filtration rate derived according to the CKD Epidemiology Collaboration; SGLT2, sodium-glucose cotransporter-2. FIDELIO-DKD
results adapted from van den Berg P et al16 under the terms of the CC-BY-NC licence (http://creativecommons.org/licenses/by-nc/4.0/).
 14631326, 0, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15387 by Nat Prov Indonesia, Wiley Online Library on [15/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 EISSING ET AL.

are summarized in Table S1. The visual predictive checks in used to model chronic eGFR decline and we could not identify addi-
Figure 4A,B indicate that the models describe the data well. tional UACR-independent finerenone effects. Accordingly, we found
The placebo models describe a UACR increase and chronic eGFR that modelled UACR accounted for 95% of finerenone's treatment
decline over time. We identified a sustained reduction in UACR as well effect on chronic eGFR decline. Based on chronic slope, finerenone's
as a slowing of chronic eGFR decline preceded by an acute eGFR treatment benefit manifested across the complete range of UACR and
decrease, reversible upon treatment discontinuation, as finerenone drug eGFR baseline values (Figure 4C,D). In general, the finerenone effect on
effects. Modelled UACR and its reduction by finerenone were then chronic slope is most pronounced at high UACR and low eGFR values.

(A)
n = 142,694 n = 19,358 n = 37,676 n = 91,332
6.5 >5.5 mmol/L=2,232 (1.6%) >5.5 mmol/L=1,378 (7.1%) >5.5 mmol/L=1,480 (3.9%) >5.5 mmol/L=1,312 (1.4%)
>6.0 mmol/L=322 (0.23%) >6.0 mmol/L=254 (1.3%) >6.0 mmol/L=198 (0.53%) >6.0 mmol/L=182 (0.2%)

6.0
Serum potassium (mmol/L)

5.5

5.0

4.5

4.0

3.5

3.0 FIDELIO-DKD FIDELITY FIGARO-DKD

Placebo Treatment interruption 10 mg 20 mg

Finerenone dose level

(B)
ACTIVE PLACEBO

6
Serum potassium (mmol/L)

0 1 2 3 4 5 0 1 2 3 4 5
Time (years)

(C) (D)
6.0 6.0
Serum potassium (mmol/L)

Serum potassium (mmol/L)

5.5 5.5

5.0 5.0

4.5 4.5

4.0 4.0

3.5 3.5
Treatment interruption 10 20 0 10 20
Dose at time of observation (mg) Dose (mg)
FIDELIO-DKD FIGARO-DKD

FIGURE 3 Legend on next page.

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EISSING ET AL. 7

A total of 1897 patients (14.6%) used a sodium-glucose
cotransporter-2 (SGLT2) inhibitor and a total of 1732 patients (13.3%)
used a glucagon-like peptide-1 receptor agonist (GLP-1RA) at or after
baseline in the FIDELIO-DKD and FIGARO-DKD studies. The effects
of time-varying SGLT2 inhibitor and GLP-1RA treatments on UACR
and eGFR were included in the model based on placebo data. Neither
SGLT2 inhibitor nor GLP-1RA treatment statistically significantly mod-
ified the effects of finerenone. Nevertheless, we included these
effects to obtain 95% CIs for potential SGLT2 inhibitor and GLP-1RA
modification of finerenone effects on UACR ranging from 3.2% to
+10.9% and from +3.5% to +17.9%, respectively, and from 31.2%
to +26.0% and from 15.7% to +10.6%, respectively, for effects on
chronic eGFR decline. The meaning of these ranges can be illustrated
by the following example: With a treatment effect of finerenone on
UACR of 100% in the absence of comedication(s), we were 95% con-
fident that the finerenone treatment effect would be between 96.8%
and 110.9% in patients using an SGLT2 inhibitor concomitantly.
Typical predicted UACR and eGFR time-courses for patients
receiving placebo, finerenone 10 and 20 mg, an SGLT2 inhibitor, and
a combination of both drugs are illustrated in Figure 4E,F. The effects
identified for single drugs and combinations including GLP-1RAs are
shown in Table 1.
were additively combined (Figure 5A,B). The first effect increased the
hazard for patients with increasing relative reduction in eGFR versus
baseline and was dependent on time after first dose, decreasing as
time increased. The second effect increased the hazard with decreas-
ing absolute eGFR. We were not able to identify eGFR-independent
effects. The two eGFR-dependent effects accounted for 87% of finer-
enone's treatment effect on the kidney outcome.
4 | DI SCU SSION
We present analyses on the relationship of finerenone dosing to PK
exposure, and then to downstream PD responses in serum potassium,
UACR and eGFR, as well as kidney outcomes based on data from the
pivotal phase 3 FIGARO-DKD and FIDELIO-DKD studies. These new
analyses extend previous studies to a broader population, providing
additional insights as well as repeating and thereby strengthening pre-
vious findings.7,16,17,19 They provide robust data on finerenone
PK/PD and dose–exposure–response relationships, increasing the
precision of estimates in a large, contemporary population of patients
with T2D and CKD.

3.4 | Kidney outcome
As the components of the composite kidney endpoint (comprising
time to the first occurrence of kidney failure, a sustained decrease in
eGFR ≥57% from baseline over at least 4 weeks, or death from kidney
causes) were mainly based on absolute eGFR levels or relative eGFR
declines from baseline, modelled eGFR should intuitively link to the
kidney outcome as supported by a parametric time-to-event model
which we developed via a hazard function that defined the individual
probability of survival at every time point.
The resulting final model described the data well and had a con-
stant base hazard, modified by two eGFR-dependent effects that
4.1 | Pharmacokinetics
The PK characteristics of finerenone in FIGARO-DKD were linear
over the studied dose range, as was previously observed in phase 1, 2
and 3 (FIDELIO-DKD) studies.16,20–24 Apart from a small influence of
kidney function decline (eGFR covariate effect on apparent clearance
and bioavailability), the long-term PK characteristics of finerenone
were not found to be time-dependent, in line with previous
analyses.16
The analyses provide a comprehensive characterization of the PK
profile in the target population (CKD and T2D) including characteriza-
tion of various covariate effects. The covariates studied generally
affected finerenone systemic exposure, with ratios to a reference

F I G U R E 3 Finerenone serum potassium pharmacokinetic-pharmacodynamic relationship in FIGARO-DKD (blue) compared to FIDELIO-DKD

(red) and pooled (green). (A) Dose–response on serum potassium box plots of central laboratory absolute potassium levels after the baseline visit
reported with one decimal. The column ‘Placebo’ shows all data for patients in the placebo arm. Stratification of the other three columns for the
active treatment arm are based on the actual dose level of the treatment at the time of the serum potassium measurement. The column
‘treatment interruption’ shows data for patients in the active treatment arm who had treatment interrupted or discontinued (permanently).
Intermittent dashed and dashed horizontal reference lines indicate 5.5 and 6.0 mmol/L, respectively, and the solid line the FIDELITY placebo
median. Pearson correlation tests were performed for each study as well as the pooled data shown, each significant with a p value < 0.001,
confirming an inverse correlation between serum potassium levels and finerenone dose levels (interrupted, 10 mg, 20 mg). (B) Finerenone and
placebo arm model predictions compared to data (visual predictive check) with data as blue dots, black lines indicating the observed median (solid
line) and 5th and 95th percentile (dashed lines), and the grey areas indicating the 99% prediction interval of the same percentiles in the
simulations, which include variability but not parameter uncertainty. (C) Visual predictive check of the dose–response of finerenone on serum
potassium for FIGARO-DKD (blue) and FIDELIO-DKD (red). Observed data are shown as points (median) and error bars (depicting the 5th and
95th percentiles); areas indicate the 99% variability-based prediction interval of simulations that include dose titration (excluding parameter
uncertainty). (D) Simulated dose–response relationship without accounting for dose titration with median and 90% prediction interval of 10 000
simulated individual predicted serum potassium levels (including interindividual variability, but not residual error) with drug effect at steady state,
ignoring the impact of disease progression. All simulated patients have typical covariates (see final model in the supplementary material). FIDELIO-
DKD results adapted from Goulooze et al.7 under the terms of the CC-BY-NC licence (http://creativecommons.org/licenses/by-nc/4.0/).
 14631326, 0, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15387 by Nat Prov Indonesia, Wiley Online Library on [15/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
8 EISSING ET AL.

(A) (B)
ACTIVE PLACEBO ACTIVE PLACEBO
100 50

CFB eGFR (mL/min/1.73 m2)

UCAR ratio versus baseline

25
10

2 0
1
0.5 –25

0.1
–50

0.01 –75
0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5
Time (years) Time (years)

(C) (D)
0.0 0

Change in chronic eGFR slope (%)

Change in chronic eGFR slope

–0.5 –10
(mL/min.1.73 m2/year)

–1.0 –20

–1.5 –30

–2.0
–40

–2.5
–50
30 45 60 75 90 105 120 30 45 60 75 90 105 120
Baseline eGFR (mL/min/1.73 m2) Baseline eGFR (mL/min/1.73 m2)

UACR 45.3 mg/g 198 mg/g 515 mg/g 1,147 mg/g 2,888 mg/g

(E) (F)
55
1.2
UACR ratio over baseline

eGFR (mL/min/1.73 m2)

1.0
50

0.8

45
0.6

0.4 40
0 1 2 3 4 0 1 2 3 4
Time (years) Time (years)
Treatment Placebo Finerenone 10 mg Finerenone 20 mg Placebo Finerenone 20 mg
(no SGLT2 inhibitor) (no SGLT2 inhibitor) (no SGLT2 inhibitor) (SGLT2 inhibitor) (SGLT2 inhibitor)

F I G U R E 4 Finerenone urine albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) pharmacokinetics-
pharmacodynamics in a pooled analysis of FIGARO-DKD and FIDELIO-DKD. Comparison of model predictions and observed data for (A) UACR
ratio versus baseline UACR and (B) eGFR change from baseline stratified by randomization to finerenone (ACTIVE) or placebo (PLACEBO) with
data as green dots, black lines indicating the observed median (solid line) and 5th and 95th percentiles (dashed lines), and the grey areas indicating
the 99% interval of the same percentiles in the simulations, which include variability but not parameter uncertainty. (C) Absolute and (D) relative
difference in chronic eGFR slope of a typical patient simulating the effect of finerenone 20 mg versus placebo for different baseline eGFR (x-axis)
and UACR (colours) values, for example, if the eGFR in a typical simulated placebo patient declines with a chronic rate of 3.0 mL/min/1.73 m2/
year, and this is reduced to a chronic decline of 2.4 mL/min/1.73 m2/year with finerenone treatment, the absolute difference is 0.6 mL/
min/1.73 m2/year and the relative change in chronic slope from finerenone treatment would be 20%, that is, finerenone slows down the rate of
eGFR decline by 20%. High UACR and low eGFR value changes are limited by patients approaching end-stage kidney failure. Illustrative simulated
profiles of (E) UACR and (F) eGFR for a typical individual treated with placebo, finerenone 10 or 20 mg and/or a sodium-glucose cotransporter-2
(SGLT2) inhibitor from time = 0 onwards without discontinuation. CFB, change from baseline.
 14631326, 0, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15387 by Nat Prov Indonesia, Wiley Online Library on [15/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
EISSING ET AL. 9

individual included in the range 0.80–1.25 in monovariate analyses.
Body weight and eGFR appear as the patient characteristic covariates
with the largest influence on finerenone exposure and in multivariate
analyses presented in this study, their influence remains limited.
T A B L E 1 Simulated effect sizes on urine albumin-creatinine ratio
and chronic estimated glomerular filtration rate decline identified for
finerenone, sodium-glucose cotransporter-2 inhibitors and glucagon-
like peptide-1 receptor agonists, as well as drug combinations.
Covariate effects, such as for SGLT2 inhibitor treatment and Korean
ethnicity as discussed based on FIDELIO-DKD,16 had a minor (and
irreproducible for ethnicity) influence on finerenone exposure, as sup-
ported by the additional FIGARO-DKD analysis included in this study.
In light of the presented exposure–response relationships and dose
titration as implemented in the trials and included in the drug label,
these effects were deemed not to be clinically relevant as reflected in
the drug label.23

Treatment (on top of Change from baseline Change in chronic

standard of care) UACR at Year 1, % eGFR slope, % 4.2 | Serum potassium
Placebo +5.2 0 (reference)
The serum potassium data and analyses strengthen previous findings
Finerenone 10 mg 32.1 17.5
OD and show how the feedback loop introduced by serum potassium-

Finerenone 20 mg 45.5 23.8 based dose titration introduces an apparent paradox, where higher
OD drug dosages are associated with less effect, that is, with lower serum
Placebo + SGLT2 18.8 43.0 potassium values in the observed clinical data.7,25
inhibitor The PK/PD model reveals the true dose–exposure–response rela-
Finerenone 20 mg 58.0 55.1 tionship, where, in simulated absence of dose titration, higher finere-
OD + SGLT2 none doses and exposures lead to higher potassium values as
inhibitor
pharmacologically expected. However, the relationship is less than
Placebo + GLP-1RA 9.0 5.7 dose-proportional, with a predicted median increase of 0.19 mmol/L
Finerenone 20 mg 52.9 26.8 on 20 mg compared to placebo in FIGARO-DKD, and inversed by
OD + GLP-1RA
dose titration as implemented in the phase 3 trials, leading to an
Note: Change in chronic eGFR slope is calculated versus a typical apparent inverse association (Pearson correlation test, p < 0.001),
FIDELITY reference patient on placebo not taking an SGLT2 inhibitor or where patients on finerenone 10 mg show higher potassium levels
GLP-1RA.
and rates of hyperkalaemia compared to patients on 20 mg. The quali-
Abbreviations: eGFR, estimated glomerular filtration rate; GLP-1RA,
glucagon-like peptide-1 receptor agonist; OD, once daily; SGLT2, sodium- tative findings from FIGARO-DKD and the pool of both phase 3 stud-
glucose cotransporter-2; UACR, urine albumin-creatinine ratio. ies are in line with previous findings based on FIDELIO-DKD.7

(A) (B)
ALL
Current probability of event during 4 months (%)

1.0 100.0
Fraction of patients not having an event

10.0
0.9

1.0
0.8

0.1
0.7
4W 3M 6M 1Y 3Y 5Y 20 40 60
Time Current eGFR (mL/min/1.73 m2)

ALL eGFR0 30 45 60 75

F I G U R E 5 Estimated glomerular filtration rate (eGFR) and kidney outcome relationship in a pooled analysis of FIGARO-DKD and FIDELIO-
DKD. (A) Visual predictive check comparing the observed survival curve of the kidney outcome (dark orange line) with the 95% interval simulated
by the model (light orange shading). (B) Predicted current probability of a 57% kidney composite endpoint over a 4-month period for different
baseline eGFR (eGFR0) values (in mL/min/1.73 m2; different colours for different baselines), plotted against current eGFR. The time dependency
of the relative effect was set to its value at 3 years after first dose. Probabilities were computed assuming a constant eGFR during the 4-month
period. At high eGFR, the probability for a kidney event is low (approximately 0.05%). At lower eGFR, the probability of the kidney event will
become higher, but the point where this happens depends on baseline eGFR: a patient with a current eGFR of 30 mL/min/1.73 m2 has lost 33%
of eGFR versus a baseline of 45 mL/min/1.73 m2, but would have lost 50% versus a baseline of 60 mL/min/1.73 m2.

10
Both the less than dose-proportional exposure–response relation-
ship and the potassium-guided titration are essential for, and explain,
the good safety profile of finerenone.5,7–9 The dose titration intro-
duces negative feedback via the treatment, which is a basic element
in control theory and in physiological systems supporting homeostasis,
including in the face of perturbations.7 Finerenone exposure is sensi-
tive to increases due to cytochrome P450 (CYP) 3A4 inhibition as
seen in Figure 2A and more prominently in dedicated evaluations,26,27
similar to eplerenone or esaxerenone. Unlike data reported for the lat-
ter MR antagonists,28 we did not find indications for increased hyper-
kalaemia rates for finerenone when co-administered with CYP3A4
inhibitors in the phase 3 studies.
4.3 | Kidney efficacy
We established progression models describing a UACR increase and
chronic eGFR decrease over time on SOC based on the pooled pla-
cebo data from FIGARO-DKD and FIDELIO-DKD. We identified finer-
enone treatment effects on top of SOC leading to a sustained
reduction in UACR, as well as a slowing down of chronic eGFR decline
preceded by an initial, reversible decrease in eGFR. This was consis-
2,3,17
tent with previously described finerenone benefits.
The PK/PD model analyses show that chronic eGFR decline is
closely associated with, and finerenone treatment effects are
explained by, (modelled) UACR in this large and heterogenous phase
17
3 pool, as previously observed in FIDELIO-DKD. In the present ana-
lyses, we further showed that the kidney outcome, including finere-
none treatment and covariate effects, can be explained to a large
extent by (modelled) eGFR. Importantly, we were not able to identify
independent finerenone treatment effects on chronic eGFR decline
beyond those reflected in modelled UACR, or on the kidney outcome
beyond those reflected in modelled eGFR. We found that modelled
UACR explained 95% of finerenone's treatment effect on chronic
eGFR decline and eGFR-dependent effects explained 87% of finere-
none's treatment effect on the kidney outcome.
While eGFR slope is directly connected to kidney outcomes eval-
uated by composite endpoints including eGFR-based components,
there are ongoing discussions on the quality of both eGFR and UACR
as surrogates, and regulators generally do not yet accept these bio-
markers as pivotal endpoints.29–31 The findings presented here further
support eGFR and UACR as surrogate markers of kidney-protective
efficacy for finerenone in CKD and T2D. The identified relationships
also describe effects in patients randomized to placebo, supporting a
relevance beyond finerenone.
The PK/PD analyses also provide evidence for the beneficial
effects of finerenone on UACR and chronic eGFR decline across dif-
ferent UACR and eGFR baseline values, as also reported for heart fail-
ure outcomes.32 Thus, in patients with a high rate of eGFR decline
(e.g., patients with a high baseline UACR), it takes less time before the
beneficial finerenone effect of reducing eGFR decline outweighs
the short-term eGFR-decreasing effect of finerenone, while the oppo-
site is true for patients with a slow rate of eGFR decline.
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EISSING ET AL.
4.4 | Co-administration with SGLT2 inhibitors and
GLP-1RAs
Assessments of continuous biomarkers can often provide higher
power than assessing binary outcome events. In the light of the pre-
sent analyses, UACR and eGFR can be considered valid surrogates for
the kidney-protective efficacy of finerenone, and to a lesser extent
the cardiovascular benefits. We therefore performed comedication
interaction analyses on these PD endpoints.
The analyses provide evidence for (largely) independent effects of
finerenone in the presence of SGLT2 inhibitor or GLP-1RA treatment.
The finerenone effects on reducing UACR in their presence are, with
97.5% confidence, at least 96.8% or 103.5% of the finerenone effects
in patients not currently using SGLT2 inhibitors or GLP-1RAs, respec-
tively. The UACR-explained finerenone effects on chronic eGFR
decline in the presence of SGLT2 inhibitors or GLP-1RAs are at least
68.8% and 84.3%, respectively, of the finerenone effects in patients
not currently on these comedications. While we also estimated effect
sizes of the comedication treatment effects themselves (Table 1),
these should be interpreted with caution, as treatment with these
drugs was not randomized and therefore was potentially subject to
selection bias. While some residual confounding cannot be completely
excluded, we consider the identified independence of effects between
SGLT2 inhibitors or GLP-1RAs and finerenone less vulnerable to bias,
because at baseline, within the subgroups of patients receiving or not
receiving these comedications, the use of finerenone versus placebo
was still randomized. In addition, covariates in the model corrected for
potential confounders.
The analyses thus provide evidence for largely independent and
additive effects of finerenone taken in combination with SGLT2 inhib-
itors and GLP-1RAs on kidney-protective efficacy. The analyses are in
line with prior PK/PD analyses as well as statistical subgroup analyses
based on treatment-by-subgroup interaction p values.16,17,33–36 They
are also in line with preclinical data as well as clinical data generated
for other MR antagonists, including finerenone,37,38,39 in combination
with an SGLT2 inhibitor. Nevertheless, it has been discussed that
additional evidence from randomized trials may be needed to further
substantiate findings and provide ‘final’ evidence.40,41 However, the
narrow CIs in the present analysis provide strong evidence in addition
to that of previous analyses. This may be considered an overall robust
set of data from which to conclude that the treatment effects of finer-
enone on kidney (and cardiovascular) benefits are largely independent
of, and additive to, SGLT2 inhibitor and GLP-1RA treatment. New
data may still provide additional insight, for example, on effects with
simultaneous initiation of finerenone and an SGLT2 inhibitor.40
4.5 | Limitations
The PK analyses were based on sparsely sampled finerenone concen-
trations. A population PK approach is the well-established standard to
analyse such data.42 We designed the PK sampling to provide maximal
information with limited samples and our assessments support model

EISSING ET AL.
and parameter identifiability (including shrinkage), stability and robust-
ness with an overall acceptable precision. Nevertheless, the sparseness
may limit the precision of maximum concentration estimates. While
most aspects of the different PK and PK/PD analyses concepts were
prespecified (see Methods), details on some aspects, such as linking
UACR to eGFR and the latter to kidney outcomes, were investigated
post hoc, which introduces the possibility of chance findings. Some
covariates were considered time-varying, introducing potential selec-
tion bias as discussed above in the context of comedication analyses,
and residual confounding cannot be excluded. Nevertheless, overall,
the data and results described are considered robust and reliable.
5 | C O N CL U S I O N
In conclusion, these analyses provide a comprehensive characteriza-
tion of the PK profile of finerenone in CKD and T2D, allowing the
estimation of individual finerenone exposure as a basis for dose–
exposure–response analyses. These analyses reveal less than dose-
proportional PK/PD relationships. They show how the potassium-
guided dose titration inverts the modelled monotonously increasing
finerenone exposure to serum potassium response relationship into
an observed inverse association, where finerenone 20 mg was associ-
ated with lower potassium levels and lower rates of hyperkalaemia
compared to 10 mg. The analyses thus also provide dose–exposure–
response insights, which would be biased in standard dose–response
analysis due to confounding in a drug-titration setting. Furthermore,
UACR and eGFR are supported as surrogates or bridging biomarkers
predictive of the kidney outcome during finerenone treatment. Evi-
dence suggests, based on narrow CIs in interaction analyses, that the
concomitant use of SGLT2 inhibitors and GLP-1RAs provides largely
independent benefits to finerenone on kidney-protective efficacy.
The ongoing CONFIDENCE trial will further elaborate on the additive
effects of dual therapy comprising finerenone and an SGLT2 inhibi-
41
tor. Overall, the analyses thus contribute to guide the safe and effi-
cacious clinical use of finerenone as described in the drug label.
AUTHOR CONTRIBUTIONS
Research idea and study design: Thomas Eissing, Sebastiaan Camiel
Goulooze, Paul van den Berg, Nelleke Snelder, Dirk Garmann, Joerg
Lippert, Meike Brinker, Roland Heinig, Hiddo J. L. Heerspink. Data
and statistical analysis or primary interpretation: Thomas Eissing,
Sebastiaan Camiel Goulooze, Paul van den Berg, Martin van Noort,
Martijn Ruppert, Nelleke Snelder. Extended interpretation/contextual-
ization, supervision or mentorship: Thomas Eissing, Dirk Garmann,
Joerg Lippert, Meike Brinker, Roland Heinig, Hiddo J. L. Heerspink.
Each author contributed important intellectual content during manu-
script drafting or revision and agrees to be personally accountable for
the individual's own contributions and to ensure that questions per-
taining to the accuracy or integrity of any portion of the work, even
one in which the author was not directly involved, are appropriately
investigated and resolved, including with documentation in the litera-
ture if appropriate.
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11
AC KNOW LEDG EME NT S
The authors thank the FIDELIO-DKD and FIGARO-DKD Committees,
investigators and patients. We are grateful to Dr. Andreas Seelmann
(Bayer), Shafi Chowdhury and team (Shafi Consultancy), and Diana
Hijdra (LAP&P) for pharmacometric analysis dataset creation, and to
Richard Hooijmaijers, Dr. Henk-Jan Drenth, Dr. Maurice Ahsman,
Dr. Jan Berkhout, Emir Mesic and Dr. Joost de Jongh (LAP&P) for sup-
port and code review. Editorial support, including figure preparation,
formatting, proofreading and submission was provided by Moamen
Hammad, PhD and Melissa Ward, BA, both of Scion, London, UK, sup-
ported by Bayer AG, Wuppertal, Germany, according to Good Publica-
tion Practice guidelines (Link). The eGFR to kidney outcome analysis
was presented in part at the Population Approach Group in Europe
(PAGE) meeting 27–30 June 2023, in A Coruña, Spain. The FIDELIO-
DKD and FIGARO-DKD trials and FIDELITY combined analyses were
sponsored by Bayer AG.
CONFLIC T OF INTER E ST STATEMENT
Thomas Eissing, Dirk Garmann, Joerg Lippert, Meike Brinker and
Roland Heinig are Bayer employees and potential shareholders of
Bayer AG. Sebastiaan Camiel Goulooze, Paul van den Berg, Martin
van Noort, Martijn Ruppert and Nelleke Snelder are employed by
LAP&P, a contract research organization working for Bayer, who con-
ducted finerenone population PK/PD analysis as contract research for
Bayer. Hiddo J. L. Heerspink co-chairs the executive committee of the
ongoing finerenone FIND-CKD trial and advises Bayer, with financial
reimbursement. He has also received grants from AstraZeneca, Boeh-
ringer Ingelheim, Janssen and Novo Nordisk, consulting fees from
AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Chinook,
Dimerix, Eli Lilly, Gilead, Goldfinch Bio, Janssen, Merck, Mitsubishi
Tanabe, Novo Nordisk and Travere Pharmaceuticals, and payment or
honoraria for speaking from AstraZeneca.
DATA AVAILABILITY STAT EMEN T
Availability of the data underlying this publication will be determined
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
patient-level clinical trial data, study-level clinical trial data, and proto-
cols from clinical trials in patients for medicines and indications
approved in the United States (US) and European Union (EU) as nec-
essary 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 01, 2014.Interested
researchers can use www.vivli.org to request access to anonymized
patient-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 stud-
ies and other relevant information is provided in the member
section of the portal.Data access will be granted to anonymized
patient-level data, protocols and clinical study reports after approval
by an independent scientific review panel. Bayer is not involved in the

12
decisions made by the independent review panel. Bayer will take all
necessary measures to ensure that patient privacy is safeguarded.
ORCID
Thomas Eissing https://orcid.org/0000-0003-4378-3423
Sebastiaan Camiel Goulooze https://orcid.org/0000-0003-3369-
6107
Nelleke Snelder https://orcid.org/0000-0003-1302-678X
Joerg Lippert https://orcid.org/0000-0002-0683-2874
Roland Heinig https://orcid.org/0000-0002-4645-5428
Meike Brinker https://orcid.org/0000-0002-1560-9535
Hiddo J. L. Heerspink https://orcid.org/0000-0002-3126-3730
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SUPPORTING INF ORMATION
Additional supporting information can be found online in the Support-
ing Information section at the end of this article.
How to cite this article: Eissing T, Goulooze SC, van den
Berg P, et al. Pharmacokinetics and pharmacodynamics of
finerenone in patients with chronic kidney disease and type 2
diabetes: Insights based on FIGARO-DKD and FIDELIO-DKD.
Diabetes Obes Metab. 2023;1‐13. doi:10.1111/dom.15387