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

Figures

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  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

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  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

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  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