TY - JOUR
T1 - Pharmacokinetics and pharmacodynamics of finerenone in patients with chronic kidney disease and type 2 diabetes
T2 - Insights based on FIGARO-DKD and FIDELIO-DKD
AU - Eissing, Thomas
AU - Goulooze, Sebastiaan Camiel
AU - van den Berg, Paul
AU - van Noort, Martijn
AU - Ruppert, Martijn
AU - Snelder, Nelleke
AU - Garmann, Dirk
AU - Lippert, Joerg
AU - Heinig, Roland
AU - Brinker, Meike
AU - Heerspink, Hiddo J.L.
N1 - Publisher Copyright:
© 2023 Bayer AG. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
PY - 2024/3
Y1 - 2024/3
N2 - 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.
AB - 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.
KW - eGFR
KW - finerenone
KW - hyperkalaemia
KW - kidney outcome
KW - serum potassium
KW - UACR
UR - http://www.scopus.com/inward/record.url?scp=85178478366&partnerID=8YFLogxK
U2 - 10.1111/dom.15387
DO - 10.1111/dom.15387
M3 - Article
C2 - 38037539
AN - SCOPUS:85178478366
SN - 1462-8902
VL - 26
SP - 924
EP - 936
JO - Diabetes, Obesity and Metabolism
JF - Diabetes, Obesity and Metabolism
IS - 3
ER -