Aldosterone, a steroid hormone, contributes to cardiorenal diseases through pro-inflammatory and fibrotic effects. Current steroidal aldosterone blockers (spironolactone and eplerenone) have limitations due to hyperkalemia and kidney dysfunction risks, especially in patients with chronic kidney disease (CKD). While showing promise in reducing albuminuria, their use is restricted, particularly when combined with ACEIs or ARBs in patients with renal insufficiency. Finerenone, a novel non-steroidal, selective mineralocorticoid receptor antagonist (MRA), offers a potential solution. It exhibits greater MRA-receptor selectivity than spironolactone and higher receptor affinity than eplerenone. Preclinical and clinical studies (ARTS) demonstrated its superior safety profile compared to spironolactone concerning serum potassium increases, along with albuminuria reduction. Further studies (ARTS-DN and ARTS-DN Japan) confirmed its efficacy in reducing albuminuria in patients with type 2 diabetes (T2D) and persistent albuminuria while receiving RAS blockers, without significant adverse effects on serum potassium or renal function. Phase I studies, however, lacked data on CKD patients and lacked pharmacodynamic focus. This study aimed to characterize pharmacokinetic variability, investigate covariate effects, and determine the PK/PD relationship with safety (serum potassium and eGFR) and efficacy parameters (UACR) in patients with T2D and CKD using data from the phase IIb ARTS-DN and ARTS-DN Japan studies. The population pharmacokinetic (popPK) model analyzed data from both studies simultaneously to describe the drug's concentration-time course and simulate dose-exposure-response relationships for relevant safety and pharmacodynamic parameters in a T2D with CKD population, simulating a Phase III scenario. Albuminuria (UACR) is a robust predictor of renal and cardiovascular risk and its reduction is strongly associated with decreased risk of ESRD and mortality.

Existing literature highlighted the benefits and limitations of steroidal mineralocorticoid receptor antagonists (MRAs) like spironolactone and eplerenone in managing cardiorenal diseases, particularly in patients with chronic kidney disease (CKD). Studies showed their efficacy in reducing albuminuria but also their potential to induce hyperkalemia and renal dysfunction, especially when used in conjunction with renin-angiotensin system (RAS) blockers. Meta-analyses confirmed the increased risk of hyperkalemia with the addition of spironolactone to ACEIs or ARBs in patients with CKD. This underscored the need for a safer and more effective MRA for this patient population. Preclinical data for finerenone indicated its favorable properties, including superior selectivity and receptor affinity compared to existing steroidal MRAs. Early clinical trials (ARTS) provided initial evidence of finerenone's safety and efficacy in reducing serum potassium increase compared to spironolactone while showing a reduction in albuminuria. However, larger scale studies focusing on T2D and CKD were needed to establish its efficacy and safety profile.

Population pharmacokinetic (PopPK)/pharmacodynamic (PopPD) models for finerenone were developed using data from the phase IIb studies, ARTS-DN (NCT01874431) and ARTS-DN Japan (NCT01968668). Phase IIa models served as a starting point. The analysis included data from all subjects in both studies, initially analyzed separately and then combined (ARTS-DN+JP). The primary efficacy endpoint was the change in UACR at 90 days, while safety markers were changes in serum potassium and eGFR. Phase IIa PK/PD models were updated with ARTS-DN data, then with the ARTS-DN+JP dataset, re-evaluating structural models as needed. The eGFR was determined using both MDRD and CKD-EPI equations, with eGFR-EPI used for exposure-response analysis and eGFR-MDRD used as a pharmacokinetic covariate. Serum potassium analysis included fractions exceeding 5.5 and 6.0 mmol/L, irrespective of study discontinuation. A hypothetical phase III scenario was simulated with defined population characteristics. A two-compartmental pharmacokinetic model with absorption through a series of transit compartments, a fixed lag time, and first-order elimination was used to describe finerenone concentration-time profiles. Covariate effects (body weight and eGFR-MDRD) were evaluated. For pharmacodynamics, different models (e.g., maximum effect, log-linear, power) were assessed for UACR, serum potassium, and eGFR, selecting the best-fitting model based on the minimum value of the objective function (MVOF). Simulations were performed for a hypothetical phase III scenario extrapolating beyond the 20mg dose and 90-day period of the ARTS-DN study.

Pharmacokinetic analysis revealed that eGFR and body weight significantly influenced finerenone pharmacokinetics, while ethnicity did not. The pharmacokinetics were dose- and time-linear. Exposure was comparable between Japanese and global populations, with only minor differences in dose-normalized AUCss and Cmaxss. For the efficacy marker UACR, a maximum effect model best described the concentration-effect relationship, showing saturation at high exposures. A log-linear model best described the relationship for serum potassium, and a power model for eGFR, both indicating attenuation of effects at high exposures. No significant ethnic differences were observed in PK/PD relationships. Time to reach 99% steady-state drug effect was 138 days for UACR, 20 days for serum potassium, and 85 days for eGFR. Simulations, extrapolating to 180 days and doses up to 30mg, showed increases in the percentage of subjects reaching target UACRs at higher doses. Increases in serum potassium and decreases in eGFR also showed a dose response, though these effects were relatively small when increasing the dose from 20mg to 30mg. Model predictions indicated that doses of 10mg and 20mg once daily were safe and effective in reducing albuminuria.

This study successfully characterized the pharmacokinetics and pharmacodynamics of finerenone in patients with T2D and CKD using a robust PopPK/PD modeling approach. The findings demonstrate that finerenone's effects on UACR, serum potassium, and eGFR show saturation or attenuation at higher doses, suggesting a dose-dependent response with limited additional benefit from exceeding 20mg once daily. The consistency of findings between the global and Japanese populations strengthens the generalizability of these results. The timescale separation between pharmacokinetic and pharmacodynamic effects highlights the importance of long-term monitoring to fully assess the drug's effects. The relatively small changes in safety parameters at higher doses support the choice of 10mg and 20mg once daily doses as safe and efficacious in reducing albuminuria. While the simulations extend beyond the clinical data, the concentration-effect relationships were well-captured up to the highest exposures, lending support to the simulation results.

PopPK/PD modeling demonstrated that finerenone's effects on UACR, serum potassium, and eGFR largely saturate around 20mg once daily. Simulations suggest limited additional benefit from increasing the dose beyond this. Doses of 10mg and 20mg once daily appear safe and effective for reducing albuminuria. Further research could explore the long-term clinical outcomes associated with these doses and investigate the potential for personalized dosing strategies based on individual patient characteristics.

The study's simulations extrapolated beyond the observed dose range and study duration, relying on the assumption that the model accurately captures the long-term effects and response at higher doses. The relatively small sample size in the Japanese study might limit the power to detect subtle ethnic differences. The study did not assess clinical outcomes directly but instead focused on surrogate markers. The use of different eGFR equations might introduce some variability.