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.

Conflict of interest statement

NS and HJD were paid consultants for Bayer AG during the conduct of the analysis. RH, AJ, PK, JL, DG, BP, and TE are employed by Bayer AG. RH, AJ, JL, DG, BP, and TE are Bayer AG shareholders.

Figures

Fig. 1

Box plot of dose-normalized a AUCss at steady state and bCmax,ss (day 30) of once-daily administration for the ARTS-DN and ARTS-DN Japan populations. The median dose-normalized AUCss and Cmax,ss values were 26.6 and 26.7 µg·h/L/mg and 6.8 and 7.3 µg/L/mg, for the ARTS-DN and ARTS-DN Japan studies, respectively. AUCss area under the plasma concentration–time curve at steady state, Cmax SS maximum concentration at steady state

Fig. 2

Predicted and observed a UACR, b absolute serum potassium concentration, and c relative change from baseline in eGFR-EPI versus finerenone AUCss. The model was fitted to individual data. For plotting purposes, the data were binned in 20 categories based on equal numbers of records. Blue dashed lines: reference/threshold lines; dark gray dashed lines: simulated AUCss for a typical subject for doses of 10, 20, and 30 mg; black solid lines: 5th and 95th percentiles of the observations; black dots: medians of the observations; red solid line and dashed lines: median predictions and 5th and 95th percentiles of the predictions; gray areas: 90% confidence intervals of the median and 5th and 95th percentiles. AUCss area under the plasma concentration–time curve at steady state, eGFR-EPI estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation, UACR urinary albumin:creatinine ratio

Fig. 3

Simulated dose–response curves for a UACR, b serum potassium concentration, and c eGFR-EPI for a phase III scenario (Table 3) following once-daily administration of placebo (0 mg) and different doses of finerenone (5.0, 7.5, 10, 15, 20, and 30 mg). Presented are the median predicted percentages of subjects (solid lines) with 90% confidence intervals (shaded areas), and the percentages of subjects reaching the thresholds following finerenone 10, 20, and 30 mg once daily. a Percentage of subjects who reach specified UACR targets at day 180. b Percentage of subjects who have one or more serum potassium concentration value > 5.5 mmol/L at any visit during treatment. c Percentage of subjects who have specified decreases from baseline in eGFR at day 180. eGFR estimated glomerular filtration rate, eGFR-EPI estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation, UACR urinary albumin:creatinine ratio