دورية أكاديمية
Pharmacokinetics and pharmacodynamics of finerenone in patients with chronic kidney disease and type 2 diabetes: Insights based on FIGARO-DKD and FIDELIO-DKD.
| العنوان: | Pharmacokinetics and pharmacodynamics of finerenone in patients with chronic kidney disease and type 2 diabetes: Insights based on FIGARO-DKD and FIDELIO-DKD. |
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| المؤلفون: | Eissing T; Bayer AG, Pharmaceuticals R&D, Pharmacometrics, Leverkusen, Germany., Goulooze SC; Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), Leiden, The Netherlands., van den Berg P; Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), Leiden, The Netherlands., van Noort M; Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), Leiden, The Netherlands., Ruppert M; Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), Leiden, The Netherlands., Snelder N; Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), Leiden, The Netherlands., Garmann D; Bayer AG, Pharmaceuticals R&D, Pharmacometrics, Leverkusen, Germany., Lippert J; Bayer AG, Pharmaceuticals R&D, Pharmacometrics, Leverkusen, Germany., Heinig R; Bayer AG, Pharmaceuticals R&D, Clinical Pharmacology, Wuppertal, Germany., Brinker M; Bayer AG, Pharmaceuticals R&D, Clinical Development, Wuppertal, Germany., Heerspink HJL; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. |
| المصدر: | Diabetes, obesity & metabolism [Diabetes Obes Metab] 2024 Mar; Vol. 26 (3), pp. 924-936. Date of Electronic Publication: 2023 Nov 30. |
| نوع المنشور: | Randomized Controlled Trial; Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 100883645 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1463-1326 (Electronic) Linking ISSN: 14628902 NLM ISO Abbreviation: Diabetes Obes Metab Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Oxford : Wiley-Blackwell, c1999- |
| مواضيع طبية MeSH: | Diabetes Mellitus, Type 2*/complications , Diabetes Mellitus, Type 2*/drug therapy , Diabetic Nephropathies* , Naphthyridines* , Renal Insufficiency, Chronic*/complications , Renal Insufficiency, Chronic*/drug therapy, Humans ; Potassium/therapeutic use ; Double-Blind Method |
| مستخلص: | 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 m 2 , 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. (© 2023 Bayer AG. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.) |
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| معلومات مُعتمدة: | Bayer AG |
| فهرسة مساهمة: | Keywords: UACR; eGFR; finerenone; hyperkalaemia; kidney outcome; serum potassium |
| المشرفين على المادة: | 0 (finerenone) 0 (Naphthyridines) RWP5GA015D (Potassium) |
| تواريخ الأحداث: | Date Created: 20231201 Date Completed: 20240208 Latest Revision: 20240208 |
| رمز التحديث: | 20240209 |
| DOI: | 10.1111/dom.15387 |
| PMID: | 38037539 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1463-1326 |
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| DOI: | 10.1111/dom.15387 |