BACKGROUND:Overactivation of the mineralocorticoid receptor is a common pathway for chronic kidney disease (CKD) progression across multiple disease aetiologies. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, has shown kidney and cardiovascular benefits in CKD due to type 2 diabetes, but its efficacy and safety across disease aetiologies, and levels of glycaemia, estimated glomerular filtration rate (eGFR), and albuminuria have not been evaluated. The aim of this study was to evaluate the efficacy and safety of finerenone across the spectrum of CKD. METHODS:We conducted an individual participant data meta-analysis of three randomised, double-blind, placebo-controlled trials of finerenone in patients with CKD: FIDELIO-DKD (NCT02540993; Sept 17, 2015, to April 14, 2020), FIGARO-DKD (NCT02545049; Sept 17, 2015, to Feb 2, 2021), and FIND-CKD (NCT05047263; Sept 21, 2021, to Feb 2, 2026). We used Cox regression models to evaluate relative effects on kidney and cardiovascular outcomes. The main kidney outcome was kidney failure or sustained 57% or more decline in eGFR; the main cardiovascular outcome was hospitalisation for heart failure or cardiovascular death. This study was registered with PROSPERO, CRD420251269149. FINDINGS:Across the three trials enrolling 14 574 participants, the mean age was 63·7 years (SD 10·6), 4467 (30·7%) were female, 10 107 (69·3%) were male, mean eGFR was 56·4 mL/min per 1·73 m2 (SD 21·4), and median urinary albumin-to-creatinine ratio was 567·4 mg/g (IQR 233·6-1164·7). Finerenone reduced the risk of the composite kidney outcome by 24% versus placebo (22·3 vs 28·8 events per 1000 patient-years; hazard ratio 0·76 [95% CI 0·68-0·86]) and kidney failure alone (0·85 [0·74-0·99]). Finerenone reduced the risk of the composite cardiovascular outcome versus placebo (19·1 vs 23·9 events per 1000 patient-years; 0·80 [0·70-0·91]), including heart failure hospitalisation (0·78 [0·66-0·92]) and cardiovascular death (0·82 [0·67-0·999]). Finerenone also reduced the risk of all-cause death (0·88 [0·79-0·99]). Treatment effects on the composite kidney outcome were consistent irrespective of glycaemic status, CKD aetiology, baseline eGFR, albuminuria, and use of sodium-glucose co-transporter-2 inhibitors. Hyperkalaemia occurred more frequently with finerenone than with placebo, but the absolute incidence of hyperkalaemia leading to hospitalisation was low. INTERPRETATION:In the studied populations with CKD, finerenone reduced the risk of CKD progression, including kidney failure alone, and reduced heart failure hospitalisation, cardiovascular death, and all-cause death. These findings support finerenone as a foundational therapy for CKD across a broad range of disease aetiologies and levels of glycaemia, eGFR, and albuminuria. FUNDING:Bayer.

Intravitreal (IVT) anti-vascular endothelial growth factor (anti-VEGF) therapies are the standard of care for retinal diseases such as neovascular age-related macular degeneration (nAMD) and diabetic macular oedema (DMO). Despite the favourable efficacy and safety profiles of these therapies, decreasing the treatment burden is still an unmet need because frequent injections may be required over many years. The pharmacokinetic and pharmacodynamic properties of IVT therapies, such as ocular half-life and clearance, can affect the duration of VEGF suppression and thus influence clinical outcomes. Although some properties are inherent to the drug molecule (such as molecular weight, binding affinity and potency) and cannot be altered without changing the structure of the molecule, other factors (such as the dose of the drug) can be increased, which may prolong VEGF suppression time in the eye and, in turn, may lead to a more durable effect of the drug. In addition to pharmacokinetic and pharmacodynamic properties, individual patient factors such as age, surgical history and disease status can also affect the pharmacokinetics, pharmacodynamics and observed effectiveness of a drug. This article reviews the key pharmacological properties of IVT anti-VEGF treatments for nAMD and DMO often referred to in the literature, and aims to elucidate their meaning and clinical relevance for managing retinal diseases.

Exposure-response (ER) analyses of repeated time-to-event (RTTE) data can be confounded when treatment modifications occur due to the event of interest. One particularly challenging scenario is when an event is preceded by an undocumented clinical worsening leading to treatment discontinuation shortly before the event. Event-related treatment modifications introduce potential reversed causality in the ER analysis and bias, as events may predict exposure, rather than exposure predicting events. We systematically evaluated three analysis approaches in multiple simulated placebo-controlled studies to assess their capacity to estimate unbiased ER relationships: (1) average exposure (2) time-varying exposure (3) average exposure + percentile-rank of the average amount of blinded study treatment received. The novel Approach 3 was designed to remove confounding from event-related treatment modifications by leveraging information on blinded study treatment received (including in the placebo treatment arm). Approach 1 was biased in all scenarios with event-related treatment discontinuations. Approach 2 generally resulted in unbiased estimates, except in the scenarios in which events were sometimes preceded by a treatment discontinuation. In these scenarios, only Approach 3 provided unbiased estimates with linear ER, though it showed slight bias with pronounced nonlinear relationships. In conclusion, treatment modifications associated with events warrant careful consideration in ER analyses of RTTE data. Using a ranked measure of the average amount of blinded study treatment received may be used to lower the risk of confounding due to treatment modifications.

Neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) can cause substantial vision loss. The 2-mg drug product of aflibercept (AFL-2)-an anti-vascular endothelial growth factor agent-has established efficacy and safety in both diseases. In pivotal trials, a high-dose drug product (AFL-HD) using a formulation distinct from AFL-2 and delivering 8-mg aflibercept every 12 or 16 weeks (following initial monthly dosing) provided visual gains non-inferior to AFL-2 administered every 8 weeks (following initial monthly dosing) and comparable safety with fewer injections over 96 weeks. Free and bound aflibercept concentrations in plasma from 2744 participants in 16 clinical trials where aflibercept was administered intravitreally, subcutaneously, or intravenously were analyzed by population pharmacokinetic modeling. A semi-mechanistic model described the release of free aflibercept from the eye and its target-mediated elimination from plasma. The evaluated covariates (weight, age, sex, albumin, disease, racial classification, Japanese origin, renal and hepatic functions) resulted in only small numerical differences in systemic exposure. Ocular clearance (QE; characterizing the bidirectional transfer of free aflibercept between the eye and central compartment) was comparable across both diseases after adjusting for an age-dependent decrease. The change in drug product, and not just the dose increase, was responsible for a 39.4% slower QE and extended exposure in the ocular space for AFL-HD versus AFL-2. The median ocular concentrations of free aflibercept predicted at the end of the 8-week dosing interval for AFL-2 were typically reached 14 weeks after AFL-HD injections, versus 9-9.5 weeks if QE was identical for both drug products.

Background There are no data on pharmacokinetics, pharmacodynamics, and immunogenicity of intravitreal aflibercept in preterm infants with retinopathy of prematurity (ROP). FIREFLEYE compared aflibercept 0.4 mg/eye and laser photocoagulation in infants with acute-phase ROP requiring treatment. Methods Infants (gestational age ≤32 weeks or birthweight ≤1500 g) with treatment-requiring ROP in ≥1 eye were randomized 2:1 to receive aflibercept 0.4 mg or laser photocoagulation at baseline in this 24-week, randomized, open-label, noninferiority, phase 3 study. Endpoints include concentrations of free and adjusted bound aflibercept in plasma, pharmacokinetic/pharmacodynamic exploration of systemic anti-vascular endothelial growth factor effects, and immunogenicity. Results Of 113 treated infants, 75 received aflibercept 0.4 mg per eye at baseline (mean chronological age: 10.4 weeks), mostly bilaterally (71 infants), and with 1 injection/eye (120/146 eyes). Concentrations of free aflibercept were highly variable, with maximum concentration at day 1, declining thereafter. Plasma concentrations of adjusted bound (pharmacologically inactive) aflibercept increased from day 1 to week 4, decreasing up to week 24. Six infants experienced treatment-emergent serious adverse events within 30 days of treatment; aflibercept concentrations were within the range observed in other infants. There was no pattern between free and adjusted bound aflibercept concentrations and blood pressure changes up to week 4. A low-titer (1:30), non-neutralizing, treatment-emergent anti-drug antibody response was reported in 1 infant, though was not clinically relevant. Conclusions 24-week data suggest intravitreal aflibercept for treatment of acute-phase ROP is not associated with clinically relevant effects on blood pressure, further systemic adverse events, or immunogenicity. ClinicalTrials.gov Identifier NCT04004208.

Plasma N-terminal prohormone B-type natriuretic peptide (NT-proBNP) concentration is a heart failure (HF) biomarker in adults and children. Its prognostic value for HF-related events has been established only in adults. Therefore, we aimed to test the hypothesis that plasma NT-proBNP concentrations predicted the risk of heart transplantation or death in children with HF. We studied the medical records of 109 children with HF enrolled in the IBM Watson Explorys database and from 150 children enrolled in the Pediatric Cardiomyopathy Registry (PCMR). Nonlinear regression was used to assess the relationship between plasma NT-proBNP concentrations and the risk of events in the two cohorts. All children in the PCMR cohort had dilated cardiomyopathy. The Explorys cohort also included children with congenital cardiovascular malformations. Median plasma NT-proBNP concentrations were 1250 pg/mL and 184 pg/mL in the Explorys and PCMR cohorts, respectively. The percentage of deaths/heart transplantations was 7%/22%, over 2 years in the Explorys cohort and 3%/16% over 5 years in the PCMR cohort. Mean estimates of plasma NT-proBNP concentration indicative of half-maximum relative risk for events (EC50 values) at 2 and 5 years were 3730 pg/mL and 4199 pg/mL, respectively, values both close to the mean of 3880 pg/mL established for adults with HF. The plasma NT-proBNP concentration is suitable for estimating relative risk of mortality and heart transplantation in children with HF, independent of etiology and shows similar relations to clinical outcomes as in adults, indicating its likely value as a surrogate marker both for adult and pediatric HF.ClinicalTrials.gov Identifiers: NCT00005391 (May 26, 2000), NCT01873976 (June 10, 2013).

Finerenone, a selective and nonsteroidal antagonist of the mineralocorticoid receptor, has received regulatory approval with the indication of cardiorenal protection in patients with chronic kidney disease associated with type 2 diabetes. It is rapidly and completely absorbed and undergoes first-pass metabolism in the gut wall and liver resulting in a bioavailability of 43.5%. Finerenone can be taken with or without food. The pharmacokinetics of finerenone are linear and its half-life is 2 to 3 h in the dose range of up to 20 mg. Cytochrome P450 (CYP) 3A4 (90%) and CYP2C8 (10%) are involved in the extensive biotransformation of finerenone to pharmacologically inactive metabolites, which are excreted via both renal (80%) and biliary (20%) routes. Moderate or severe renal impairment, or moderate hepatic impairment result in area-under-the-curve increases of finerenone (< 40%), which do not require a dose adjustment per se, as the starting dose is based on estimated glomerular filtration rate (eGFR) and titrated according to serum potassium levels and eGFR decline. No relevant effects of age, sex, body size or ethnicity on systemic finerenone exposure were identified. Modulators of CYP3A4 activity were found to affect finerenone exposure, consistent with its classification as a sensitive CYP3A4 substrate. Serum potassium should be monitored during drug initiation or dosage adjustment of either a moderate or weak CYP3A4 inhibitor or finerenone, and the dose of finerenone should be adjusted as appropriate. Its use with strong inhibitors is contraindicated and strong or moderate inducers of CYP3A4 should be avoided. Finerenone has no potential to affect relevant CYP enzymes and drug transporters.

Background The objectives of this study were to use electronic health record data from a US national multicenter pediatric network to identify a large cohort of children with CKD, evaluate CKD progression, and examine clinical risk factors for kidney function decline. Methods This retrospective cohort study identified children seen between January 1, 2009, to February 28, 2022. Data were from six pediatric health systems in PEDSnet. We identified children aged 18 months to 18 years who met criteria for CKD: two eGFR values <90 and ≥15 ml/min per 1.73 m 2 separated by ≥90 days without an intervening value ≥90. CKD progression was defined as a composite outcome: eGFR <15 ml/min per 1.73 m 2 , ≥50% eGFR decline, long-term dialysis, or kidney transplant. Subcohorts were defined based on CKD etiology: glomerular, nonglomerular, or malignancy. We assessed the association of hypertension (≥2 visits with hypertension diagnosis code) and proteinuria (≥1 urinalysis with ≥1+ protein) within 2 years of cohort entrance on the composite outcome. Results Among 7,148,875 children, we identified 11,240 (15.7 per 10,000) with CKD (median age 11 years, 50% female). The median follow-up was 5.1 (interquartile range 2.8–8.3) years, the median initial eGFR was 75.3 (interquartile range 61–83) ml/min per 1.73 m 2 , 37% had proteinuria, and 35% had hypertension. The following were associated with CKD progression: lower eGFR category (adjusted hazard ratio [aHR] 1.44 [95% confidence interval (95% CI), 1.23 to 1.69], aHR 2.38 [95% CI, 2.02 to 2.79], aHR 5.75 [95% CI, 5.05 to 6.55] for eGFR 45–59 ml/min per 1.73 m 2 , 30–44 ml/min per 1.73 m 2 , 15–29 ml/min per 1.73 m 2 at cohort entrance, respectively, when compared with eGFR 60–89 ml/min per 1.73 m 2 ), glomerular disease (aHR 2.01 [95% CI, 1.78 to 2.28]), malignancy (aHR 1.79 [95% CI, 1.52 to 2.11]), proteinuria (aHR 2.23 [95% CI, 1.89 to 2.62]), hypertension (aHR 1.49 [95% CI, 1.22 to 1.82]), proteinuria and hypertension together (aHR 3.98 [95% CI, 3.40 to 4.68]), count of complex chronic comorbidities (aHR 1.07 [95% CI, 1.05 to 1.10] per additional comorbid body system), male sex (aHR 1.16 [95% CI, 1.05 to 1.28]), and younger age at cohort entrance (aHR 0.95 [95% CI, 0.94 to 0.96] per year older). Conclusions In large-scale real-world data for children with CKD, disease etiology, albuminuria, hypertension, age, male sex, lower eGFR, and greater medical complexity at start of follow-up were associated with more rapid decline in kidney function.

AIMS:To perform dose-exposure-response analyses to determine the effects of finerenone doses. MATERIALS AND METHODS:Two randomized, double-blind, placebo-controlled phase 3 trials enrolling 13 026 randomized participants with type 2 diabetes (T2D) from global sites, each with an estimated glomerular filtration rate (eGFR) of 25 to 90 mL/min/1.73 m2 , a urine albumin-creatinine ratio (UACR) of 30 to 5000 mg/g, and serum potassium ≤ 4.8 mmol/L were included. Interventions were titrated doses of finerenone 10 or 20 mg versus placebo on top of standard of care. The outcomes were trajectories of plasma finerenone and serum potassium concentrations, UACR, eGFR and kidney composite outcomes, assessed using nonlinear mixed-effects population pharmacokinetic (PK)/pharmacodynamic (PD) and parametric time-to-event models. RESULTS:For potassium, lower serum levels and lower rates of hyperkalaemia were associated with higher doses of finerenone 20 mg compared to 10 mg (p < 0.001). The PK/PD model analysis linked this observed inverse association to potassium-guided dose titration. Simulations of a hypothetical trial with constant finerenone doses revealed a shallow but increasing exposure-potassium response relationship. Similarly, increasing finerenone exposures led to less than dose-proportional increasing reductions in modelled UACR. Modelled UACR explained 95% of finerenone's treatment effect in slowing chronic eGFR decline. No UACR-independent finerenone effects were identified. Neither sodium-glucose cotransporter-2 (SGLT2) inhibitor nor glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment significantly modified the effects of finerenone in reducing UACR and eGFR decline. Modelled eGFR explained 87% of finerenone's treatment effect on kidney outcomes. No eGFR-independent effects were identified. CONCLUSIONS:The analyses provide strong evidence for the effectiveness of finerenone dose titration in controlling serum potassium elevations. UACR and eGFR are predictive of kidney outcomes during finerenone treatment. Finerenone's kidney efficacy is independent of concomitant use of SGLT2 inhibitors and GLP-1RAs.

Finerenone is a nonsteroidal, selective mineralocorticoid receptor antagonist that recently demonstrated its efficacy to delay chronic kidney disease (CKD) progression and reduce cardiovascular events in patients with CKD and type 2 diabetes. Here, we report the development of a physiologically-based pharmacokinetic (PBPK) model for finerenone and its application as a victim drug of cytochrome P450 3A4 (CYP3A4)-mediated drug-drug interactions (DDIs) using the open-source PBPK platform PK-Sim, which has recently been qualified for this application purpose. First, the PBPK model for finerenone was developed using physicochemical, in vitro, and clinical (including mass balance) data. Subsequently, the finerenone model was validated regarding the contribution of CYP3A4 metabolism to total clearance by comparing to observed data from dedicated clinical interaction studies with erythromycin (simulated geometric mean ratios of the area under the plasma concentration-time curve [AUCR] of 3.46 and geometric mean peak plasma concentration ratios [Cmax Rs] of 2.00 vs. observed of 3.48 and 1.88, respectively) and verapamil (simulated AUCR of 2.91 and Cmax R of 1.86 vs. observed of 2.70 and 2.22, respectively). Finally, the finerenone model was applied to predict clinically untested DDI studies with various CYP3A4 modulators. An AUCR of 6.31 and a Cmax R of 2.37 was predicted with itraconazole, of 5.28 and 2.25 with clarithromycin, 1.59 and 1.40 with cimetidine, 1.57 and 1.38 with fluvoxamine, 0.19 and 0.32 with efavirenz, and 0.07 and 0.14 with rifampicin. This PBPK analysis provides a quantitative basis to guide the label and clinical use of finerenone with concomitant CYP3A4 modulators.

Finerenone reduces the risk of kidney failure in patients with chronic kidney disease and type 2 diabetes. Changes in the urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are surrogates for kidney failure. We performed dose–exposure–response analyses to determine the effects of finerenone on these surrogates in the presence and absence of sodium glucose co-transporter-2 inhibitors (SGLT2is) using individual patient data from the FIDELIO-DKD study. Non-linear mixed-effects population pharmacokinetic/pharmacodynamic models were used to quantify disease progression in terms of UACR and eGFR during standard of care and pharmacodynamic effects of finerenone in the presence and absence of SGLT2i use. The population pharmacokinetic/pharmacodynamic models adequately described effects of finerenone exposure in reducing UACR and slowing eGFR decline over time. The reduction in UACR achieved with finerenone during the first year predicted its subsequent effect in slowing progressive eGFR decline. SGLT2i use did not modify the effects of finerenone. The population pharmacokinetic/pharmacodynamic model demonstrated with 97.5% confidence that finerenone was at least 94.1% as efficacious in reducing UACR in patients using an SGLT2i compared with patients not using an SGLT2i based on the 95% confidence interval of the SGLT2i-finerenone interaction from 94.1 to 122%. The 95% confidence interval of the SGLT2i-finerenone interaction for the UACR-mediated effect on chronic eGFR decline was 9.5–144%. We developed a model that accurately describes the finerenone dose–exposure–response relationship for UACR and eGFR. The model demonstrated that the early UACR effect of finerenone predicted its long-term effect on eGFR decline. These effects were independent of concomitant SGLT2i use.

The Open Systems Pharmacology Suite contains different software tools with its main components being PK-Sim® and MoBi®. PK-Sim® includes the most relevant and “standardized” approaches for physiologically based pharmacokinetic modeling, enabling the simulation of drug concentrations in preclinical species as well as in human. One important part of the predefined model structure in PK-Sim® is the sub-model for gastrointestinal transit and absorption. This chapter discusses a selection of the most relevant physiological parameters important for the oral administration of modified-release formulations, focusing especially on those parameters defining the intestinal permeability and the active processes that can be included in the model. The dissolved form assumes that the drug is administered as a solution and that the drug is already completely dissolved. The zero and first-order dissolution functions are simple empirical equations that define the corresponding release kinetics. The particle dissolution formulation is a mechanistic description of the dissolution processes available in PKSim®.

Purpose To investigate whether vascular endothelial growth factor (VEGF)–suppression durations contribute to our understanding of clinical trial outcomes by simulating vitreous molar concentrations (Cvm) of intravitreal aflibercept (IVT-AFL) and brolucizumab (IVT-BRO) using pharmacokinetic (PK) modeling. Methods A PK model simulated Cvm after single-dose IVT-AFL, IVT-BRO, and ranibizumab (IVT-RAN), and extrapolated intraocular VEGF-suppression thresholds and durations. Vitreous PK after multidose regimens used in studies of IVT-AFL versus IVT-BRO were simulated and compared with best-corrected visual acuity (BCVA) data. Results Cvm peaked higher (Cmax) and decreased more quickly to the VEGF-suppression threshold and minimum (Cmin) levels with IVT-BRO than with IVT-AFL, consistent with their molar doses calculated using molecular weights and vitreous half-lives (26 kDa and 115 kDa; 4.4–5.1 and 9.1–11 days, respectively). The mean VEGF suppression durations were 71 days for IVT-AFL 2 mg and 51 (48–59) days for IVT-BRO 6 mg. Based on dosing in OSPREY (matched dosing to week [w]32 for both agents; thereafter, IVT-AFL every eight weeks [q8w] and IVT-BRO q12w for the last two doses [w32→w44 and w44→w56]), IVT-BRO showed wider Cmax-Cmin fluctuations than IVT-AFL. The IVT-BRO Cmin fell below the VEGF-suppression threshold at timepoints near w56, when decreases in BCVA were also observed. The IVT-AFL vitreous Cmin remained above the suppression threshold through w56, where BCVA gains were maintained. Conclusions The PK-modeled mean VEGF-suppression duration for IVT-BRO was substantially shorter than that published for IVT-AFL and may not be sufficient to effectively suppress VEGF throughout q12w dosing. Translational Relevance The PK modeling suggests that more patients may be maintained on ≥q12w dosing with IVT-AFL than with IVT-BRO.

Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist (MRA) that demonstrated efficacy in delaying the progression of chronic kidney disease (CKD) and reducing cardiovascular events in patients with CKD and type 2 diabetes mellitus in FIDELIO-DKD, where 5734 patients were randomized 1:1 to receive either finerenone or placebo, with a median follow-up of 2.6 years. Doses of finerenone 10 or 20 mg once daily were titrated based on (serum) potassium and estimated glomerular filtration rate. The MRA mode of action increases potassium. Nonlinear mixed-effects population pharmacokinetic/pharmacodynamic models were used to analyze the finerenone dose–exposure–response relationship for potassium in FIDELIO-DKD. Individual time-varying exposures from pharmacokinetic analyses were related to the potassium response via a maximal effect, indirect-response model informed by 148,384 serum potassium measurements. Although observed potassium levels decreased with increasing dose (i.e., inverse relation), model-based simulations for a fixed-dose setting (i.e., no dose titration) revealed the intrinsic finerenone dose–exposure–potassium response, with potassium levels increasing in a dose- and exposure-dependent manner, thus explaining the apparent conflict. The potassium limit for inclusion and uptitration from finerenone 10 to 20 mg in FIDELIO-DKD was ≤ 4.8 mmol/L. Modified limits of ≤ 5.0 mmol/L were simulated, resulting in higher hyperkalemia frequencies for both the finerenone and the placebo arms, whereas the relative hyperkalemia risk of a finerenone treatment compared with placebo did not increase. The analyses demonstrated the effectiveness of finerenone dose titration in managing serum potassium and provide a quantitative basis to guide safe clinical use.

Finerenone 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. Nonlinear 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. The 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. None 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.

Development and guidance of dosing schemes in children have been supported by physiology-based pharmacokinetic (PBPK) modeling for many years. PBPK models are built on a generic basis, where compound- and system-specific parameters are separated and can be exchanged, allowing the translation of these models from adults to children by accounting for physiological differences. Owing to these features, PBPK modeling is a valuable approach to support clinical decision making for dosing in children. In this analysis, we evaluate pediatric PBPK models for 10 small-molecule compounds that were applied to support clinical decision processes at Bayer for their predictive power in different age groups. Ratios of PBPK-predicted to observed PK parameters for the evaluated drugs in different pediatric age groups were estimated. Predictive performance was analyzed on the basis of a 2-fold error range and the bioequivalence range (ie, 0.8 ≤ predicted/observed ≤ 1.25). For all 10 compounds, all predicted-to-observed PK ratios were within a 2-fold error range (n = 27), with two-thirds of the ratios within the bioequivalence range (n = 18). The findings demonstrate that the pharmacokinetics of these compounds was successfully and adequately predicted in different pediatric age groups. This illustrates the applicability of PBPK for guiding dosing schemes in the pediatric population.

N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) is a well‐established biomarker in heart failure (HF) but controversially discussed as a potential surrogate marker in HF trials. We analyzed the NT‐proBNP/mortality relationship in real‐world data (RWD) of 108,330 HF patients from the IBM Watson Health Explorys database and compared it with the NT‐proBNP / clinical event end‐point relationship in 20 clinical HF studies. With a hierarchical statistical model, we quantified the functional relationship and interstudy variability. To independently qualify the model, we predicted outcome hazard ratios in five phase III HF studies solely based on NT‐proBNP measured early in the respective study. In RWD and clinical studies, the relationship between NT‐proBNP and clinical outcome is well described by an E max model. The NT‐proBNP independent baseline risk (R 0 , RWD/studies median (interstudy interquartile range): 5.5%/3.0% (1.7–4.9%)) is very low compared with the potential NT‐proBNP–associated maximum risk (R max : 55.2%/79.4% (61.5–89.0%)). The NT‐proBNP concentration associated with the half‐maximal risk is comparable in RWD and across clinical studies (EC 50 : 3,880/2,414 pg/mL (1,460–4,355 pg/mL)). Model‐based predictions of phase III outcomes, relying on short‐term NT‐proBNP data only, match final trial results with comparable confidence intervals. Our analysis qualifies NT‐proBNP as a surrogate for clinical outcome in HF trials. NT‐proBNP levels after short treatment durations of less than 10 weeks quantitatively predict hazard ratios with confidence levels comparable to final trial readout. Early NT‐proBNP measurement can therefore enable shorter and smaller but still reliable HF trials.