Dataset Information

Population Pharmacokinetic and Exposure-Response Analysis of Finerenone: Insights Based on Phase IIb Data and Simulations to Support Dose Selection for Pivotal Trials in Type 2 Diabetes with Chronic Kidney Disease.

ABSTRACT:

Background

Finerenone (BAY 94-8862) is a potent non-steroidal, selective mineralocorticoid receptor antagonist being developed for the treatment of patients with type 2 diabetes and chronic kidney disease.

Methods

We present the population pharmacokinetics and pharmacodynamics (PD) analysis for efficacy and safety markers based on data from two clinical phase IIb studies: ARTS-DN (NCT01874431) and ARTS-DN Japan (NCT01968668).

Results

The pharmacokinetics of finerenone were adequately characterized, with estimated glomerular filtration rate (eGFR) and body weight as influencing covariates. The area under the plasma concentration-time curve in Japanese patients did not differ from that in the global population, and the investigated pharmacokinetics were dose- and time-linear. In addition, the pharmacokinetic model provided robust individual exposure estimates to study exposure-response. The concentration-effect relationship over time for the efficacy marker urinary albumin:creatinine ratio (UACR) was well-characterized by a maximum effect model indicating saturation at high exposures. For the safety markers, a log-linear model and a power model were identified for serum potassium concentration and eGFR, respectively, indicating attenuation of effect gains at high exposures. There was no apparent ethnic effect on the investigated pharmacokinetic-pharmacodynamic relationships. The model-predicted times to reach the full (99%) steady-state drug effect on UACR, serum potassium, and eGFR were 138, 20, and 85 days, respectively, while the pharmacokinetic half-life was 2-3 h and steady state was achieved after 2 days, indicating timescale separation.

Conclusion

Our dose-exposure-response modeling and simulation indicates effects were largely saturated at finerenone 20 mg and doses of both 10 and 20 mg once daily appear safe and efficacious at reducing albuminuria.

SUBMITTER: Snelder N

PROVIDER: S-EPMC7051931 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Population Pharmacokinetic and Exposure-Response Analysis of Finerenone: Insights Based on Phase IIb Data and Simulations to Support Dose Selection for Pivotal Trials in Type 2 Diabetes with Chronic Kidney Disease.

Snelder Nelleke N Heinig Roland R Drenth Henk-Jan HJ Joseph Amer A Kolkhof Peter P Lippert Jörg J Garmann Dirk D Ploeger Bart B Eissing Thomas T

Clinical pharmacokinetics 20200301 3

<h4>Background</h4>Finerenone (BAY 94-8862) is a potent non-steroidal, selective mineralocorticoid receptor antagonist being developed for the treatment of patients with type 2 diabetes and chronic kidney disease.<h4>Methods</h4>We present the population pharmacokinetics and pharmacodynamics (PD) analysis for efficacy and safety markers based on data from two clinical phase IIb studies: ARTS-DN (NCT01874431) and ARTS-DN Japan (NCT01968668).<h4>Results</h4>The pharmacokinetics of finerenone were ...[more]

PMID: 31583611

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Project description:BackgroundFinerenone 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.MethodsNonlinear 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.ResultsThe 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.ConclusionsNone 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.

Project description:Background: Chronic kidney disease (CKD) is a global public health issue. In recent years, the effectiveness of finerenone for treatment of CKD has been the subject of considerable debate. The main objective of the current meta-analysis was to validate the clinical efficacy and safety of finerenone in patients with CKD. Methods: Seven databases were searched for randomized controlled trials (RCTs) comparing finerenone with placebo in patients with CKD. Data from eligible studies were extracted, and the Cochrane risk of bias tool utilized for evaluating the methodological quality of RCTs. The effect size was estimated using the risk ratio (RR) and mean difference (MD) with 95% confidence interval (CI). Results: Five trials (n = 13,078) were included. Compared to placebo groups, the urinary albumin-to-creatinine ratio (UACR) mean from the baseline was significantly lower [MD -0.30 (95% CI -0.32, -0.28), p < 0.00001], while a decrease in the estimated glomerular filtration rate (eGFR) from baseline was significantly higher [MD -2.44 (95% CI -2.82, -2.05), p < 0.00001] for the finerenone groups. Furthermore, the proportion of patients with decreased eGFR (≥40%) post-baseline was significantly lower [RR 0.85 (95% CI 0.78, 0.93), p = 0.0002], along with end-stage kidney disease (ESKD) [RR 0.80 (95% CI 0.65, 0.99), p = 0.04] and cardiovascular events (CVs) [RR 0.88 (95% CI 0.80, 0.95), p < 0.003] in the finerenone groups. In terms of safety, the increase in the serum potassium concentration and incidence of hyperkalemia was significantly higher for the finerenone groups [MD 0.17 (95% CI 0.10, 0.24), p < 0.00001; RR 2.03 (95% CI 1.83, 2.26), p < 0.00001, respectively], but the incidence of adverse events (AEs) was similar to placebo [RR 1.00 (95% CI 0.98-1.01), p = 0.67]. In all cases, the results were rated as providing moderate-quality or high-quality evidence. Conclusion: Data from our meta-analysis suggest that finerenone confers significant renal and cardiovascular benefits in patients with CKD. While higher risk of hyperkalemia was observed with finerenone than placebo, differences in AEs were not significant. Finerenone may therefore present a novel promising therapeutic agent for patients with CKD. Systematic Review Registration: [https://inplasy.com/inplasy-2021-9-0020/], identifier [INPLASY202190020].

Dataset Information

Population Pharmacokinetic and Exposure-Response Analysis of Finerenone: Insights Based on Phase IIb Data and Simulations to Support Dose Selection for Pivotal Trials in Type 2 Diabetes with Chronic Kidney Disease.

Background

Methods

Results

Conclusion

Publications

Population Pharmacokinetic and Exposure-Response Analysis of Finerenone: Insights Based on Phase IIb Data and Simulations to Support Dose Selection for Pivotal Trials in Type 2 Diabetes with Chronic Kidney Disease.

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