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

Aldosterone is a steroid hormone that, apart from its renal effects on sodium retention and potassium excretion, exerts important pro-inflammatory/-fibrotic effects contributing to the pathogenesis of cardiorenal diseases. The current steroidal aldosterone blockers (i.e., mineralocorticoid receptor [MR] antagonists [MRAs]) spironolactone and eplerenone have a class I recommendation for patients with chronic heart failure (CHF) and a reduced left ventricular function (heart failure with reduced ejection fraction [HFrEF]). However, their use is limited due to the potential development of hyperkalemia (i.e., an increase of serum potassium above 5.5 mmol/L) and kidney dysfunction, particularly when given on top of standard of care such as angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) among patients with concomitant renal insufficiency. This intrinsic risk is even more relevant for patients with chronic kidney disease (CKD). On the other hand, small exploratory clinical studies demonstrated significant reduction of the most important pharmacodynamic parameter albuminuria/proteinuria in these patients. In fact, addition of spironolactone to ACEIs and/or ARBs was found to increase the risk of hyperkalemia three-fold in patients with CKD, as deduced from a comprehensive meta-analysis [1].

Finerenone is a novel, potent, non-steroidal, selective MRA being developed for the treatment of patients with type 2 diabetes (T2D) and CKD. Compared with currently available steroid-based MRAs, it has greater MRA-receptor selectivity than spironolactone and higher receptor affinity than eplerenone in vitro [2]. Favorable properties were shown in preclinical studies [3], and clinically in ARTS (minerAlocorticoid Receptor antagonist Tolerability Study), where finerenone doses of 2.5–10 mg/day were shown to lead to significantly smaller mean increases in serum potassium than spironolactone (mean dose 37 mg/day) in patients with CHF and CKD stage III. As an exploratory outcome, a reducing effect on albuminuria from baseline was observed with finerenone compared with placebo [4]. The efficacy and safety were further investigated in ARTS-DN (ARTS-Diabetic Nephropathy), in which different once-daily (OD) oral doses of finerenone and placebo were given to patients with T2D and persistent albuminuria (urinary albumin:creatinine ratio [UACR] ≥ 30 mg/g) receiving a renin–angiotensin system (RAS) blocker; the addition of finerenone resulted in a dose-dependent reduction in UACR that was statistically significant compared with placebo for the 7.5–20 mg OD doses [5]. Similar results were obtained in the Japanese study (ARTS-DN Japan), in which finerenone again reduced albuminuria, without adverse effects on serum potassium levels or renal function, in Japanese patients with T2D and CKD [6]. The safety, tolerability, and pharmacokinetics of finerenone were evaluated in healthy male volunteers in two randomized, single-center studies spanning a dose range of 1–80 mg showing dose-linear pharmacokinetics with rapid absorption and elimination [7]. In a renal impairment study, exposure to finerenone was not affected by mild renal impairment, whereas moderate or severe renal impairment increased integral exposure with moderate-to-high inter-individual variability, without a consistent effect on maximum concentration (C_max). Renal elimination of finerenone is minimal (less than 1% of dose). However, changes in exposure may occur because of the effects of renal impairment on non-renal routes of elimination [8]. In a hepatic impairment study, finerenone area under the plasma concentration–time curve (AUC) and unbound finerenone AUC were 38% and 55% greater, respectively, in participants with moderate hepatic impairment than in healthy participants, whereas C_max was unchanged. No clear effects on AUC or C_max were seen in participants with mild hepatic impairment [9]. Crossover studies assessed the mass balance, absolute bioavailability, and effects of erythromycin, verapamil, and gemfibrozil on the systemic exposure of finerenone, complemented by in vitro studies [10, 11].

The phase I studies with pharmacokinetic components did not include patients with CKD, and thus no relevant pharmacodynamics were expected. Although providing initial evidence of safety and efficacy, ARTS was not focused on T2D with CKD. The aim of the present study was to use the sparse data collected in the phase IIb ARTS-DN and ARTS-DN Japan studies and characterize pharmacokinetic variability, investigate covariate effects, and discern the pharmacokinetic/pharmacodynamic (PK/PD) relationship to relevant safety (serum potassium and estimated glomerular filtration rate [eGFR]) and efficacy parameters (UACR) in adult patients with T2D and CKD. Increasing albuminuria as measured by UACR is a robust predictor of renal and cardiovascular risk, and retrospective and observational studies have demonstrated a strong association between changes in albuminuria and risk of end-stage renal disease (ESRD) and mortality [12‐15]. A population pharmacokinetic (popPK) model utilized data from all subjects of the phase IIb ARTS-DN and ARTS-DN Japan studies simultaneously to characterize the concentration–time course of the drug for both the study population and individual subjects [16]. The developed model was further applied to simulate the dose–exposure–response relationships for relevant safety and pharmacodynamic parameters in a T2D with CKD study population as a phase III scenario.

PopPK/pharmacodynamic (PopPK/PD) models for finerenone were developed continuously alongside its clinical development (Table 1). The models identified, based on clinical phase I and IIa data, served as a starting point for the current analysis. Relevant information on the model development history is presented in Electronic Supplementary Material (ESM) Phase IIa Models.

The current analysis focuses on data from the two phase IIb studies, ARTS-DN (NCT01874431) and ARTS-DN Japan (NCT01968668). ARTS-DN was a global study that did not include patients from Japan, who were investigated in the dedicated study ARTS-DN Japan. Dose–exposure–response analyses were first conducted on ARTS-DN data alone, and then on a combined ARTS-DN and ARTS-DN Japan dataset termed ARTS-DN^+JP hereafter. Further details on the studies, including analytical methods, are summarized in the ESM Methods and have been published in more detail previously [5, 6, 17]. Tables 2 and 3 provide summary characteristics and statistics of the studies relevant for the analysis presented here. The primary efficacy endpoint in these studies was effect of treatment on UACR after 90 days compared with baseline; the main safety markers were change in serum potassium concentration and eGFR.

For the current analysis, the phase IIa pharmacokinetic and PK/PD models for the aforementioned markers (ESM Phase IIa Models) were updated by parameter estimation first with ARTS-DN data, and then using the ARTS-DN^+JP dataset (Tables 2 and 3) and, if needed, the structural models were re-evaluated. Additional information on model development, simulation specifications, and computational tools used are presented in the ESM Methods. Confidence intervals (CIs) throughout the text correspond to 90% CIs. For simulations, a hypothetical phase III scenario has been considered with population characteristics as defined in Table 4.

Notably, two different methods were used to derive eGFR. The eGFR derived using the Modification of Diet in Renal Disease (MDRD) study equation (here termed eGFR-MDRD) is historically the more widely used biomarker [18‐20], whereas eGFR according to the CKD Epidemiology Collaboration (CKD-EPI) equation (here termed eGFR-EPI) is calculated using a more recent formula more specific for CKD [21, 22] (see also Eqs. S9 and S10 in the ESM Functional Forms). The ARTS-DN studies evaluated eGFR-EPI and this was used in the exposure–response analysis presented here. For consistency and comparability with historical finerenone studies analyzed with popPK models, eGFR-MDRD was used as a covariate for pharmacokinetics in the popPK analysis presented here.

Also of note, in the current analysis serum potassium was fitted and simulated and population fractions crossing thresholds of 5.5 and 6.0 mmol/L were derived irrespective of study continuation, as further detailed in the ESM Methods. This does not directly correspond to the prespecified secondary outcome of hyperkalemia in ARTS-DN that included study discontinuation [5].

Population pharmacokinetic and PK/PD models were developed to characterize the pharmacokinetics of finerenone and its effect on UACR, serum potassium concentration, and eGFR in patients with T2D and CKD using data from the phase IIb ARTS-DN global and Japan studies, including a comparison of the two studies. The developed models were further used to simulate the dose–exposure–response relationships for the biomarkers in a study population with T2D and CKD as a phase III scenario.

Methods based on predefined event counting generally consider the data at one timepoint, visit, or dose group, whereas continuous PK/PD models take the totality of the data into account. For this reason, PK/PD models can be considered more robust than predefined event counting methods.

The pharmacokinetics of finerenone and its effects on UACR, serum potassium concentration, and eGFR were adequately described by popPK and popPK/PD models in the ARTS-DN and ARTS-DN Japan populations. Model analyses indicate that the pharmacological effects on reducing the efficacy marker UACR, as well as effects on safety parameters increasing serum potassium concentration and decreasing eGFR, generally approach saturation or attenuate towards the highest dose of 20 mg OD investigated in ARTS-DN. Simulations demonstrated that increasing the dose beyond 20 mg OD to 30 mg OD would result in relatively small additional increases in the percentage of subjects reaching efficacy targets and safety thresholds. It is difficult to evaluate to what degree a small incremental decrease in UACR would translate into clinically meaningful benefit, also considering potentially counteracting effects on clinical efficacy from increased serum potassium and decreased eGFR, and in addition the potential decrease in tolerability in progressive kidney disease. Doses of both 10 and 20 mg OD appeared safe and efficacious at reducing albuminuria. PopPK/PD models are in place to investigate the dose–exposure–response relationship in phase III for relevant efficacy and safety parameters and link these to clinical outcomes.