دورية أكاديمية
Dose-Exposure-Response Analysis of the Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone on UACR and eGFR: An Analysis from FIDELIO-DKD.
العنوان: | Dose-Exposure-Response Analysis of the Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone on UACR and eGFR: An Analysis from FIDELIO-DKD. |
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المؤلفون: | Goulooze SC; Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), Leiden, The Netherlands., Heerspink HJL; Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., van Noort 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., Brinker M; Bayer AG, Pharmaceuticals R&D, Clinical Development, Leverkusen, Germany., Lippert J; Bayer AG, Pharmaceuticals R&D, Pharmacometrics, Building B106, Room 205, 51368, Leverkusen, Germany., Eissing T; Bayer AG, Pharmaceuticals R&D, Pharmacometrics, Building B106, Room 205, 51368, Leverkusen, Germany. thomas.eissing@bayer.com. |
المصدر: | Clinical pharmacokinetics [Clin Pharmacokinet] 2022 Jul; Vol. 61 (7), pp. 1013-1025. Date of Electronic Publication: 2022 May 05. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Country of Publication: Switzerland NLM ID: 7606849 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1179-1926 (Electronic) Linking ISSN: 03125963 NLM ISO Abbreviation: Clin Pharmacokinet Subsets: MEDLINE |
أسماء مطبوعة: | Publication: [Switzerland] : Adis, part of Springer Science+Business Media Original Publication: New York, ADIS Press. |
مواضيع طبية MeSH: | Diabetes Mellitus, Type 2*/complications , Diabetes Mellitus, Type 2*/drug therapy , Renal Insufficiency*/complications , Renal Insufficiency, Chronic*/drug therapy , Sodium-Glucose Transporter 2 Inhibitors*, Glomerular Filtration Rate ; Humans ; Mineralocorticoid Receptor Antagonists/pharmacology ; Mineralocorticoid Receptor Antagonists/therapeutic use ; Naphthyridines |
مستخلص: | Background and Objective: 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. Methods: 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. Results: 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%. Conclusions: 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. (© 2022. The Author(s).) |
References: | Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295–306. (PMID: 10.1056/NEJMoa1811744) Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–46. (PMID: 10.1056/NEJMoa2024816) Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219–29. (PMID: 10.1056/NEJMoa2025845) Thompson A, Smith K, Lawrence J. Change in estimated GFR and albuminuria as end points in clinical trials: a viewpoint from the FDA. Am J Kidney Dis. 2020;75(1):4–5. (PMID: 10.1053/j.ajkd.2019.08.007) Holtkamp F, Gudmundsdottir H, Maciulaitis R, Benda N, Thomson A, Vetter T. Change in albuminuria and estimated GFR as end points for clinical trials in early stages of CKD: a perspective from European regulators. Am J Kidney Dis. 2020;75(1):6–8. (PMID: 10.1053/j.ajkd.2019.07.019) Levey AS, Gansevoort RT, Coresh J, Inker LA, Heerspink HL, Grams ME, et al. Change in albuminuria and GFR as end points for clinical trials in early stages of CKD: a scientific workshop sponsored by the National Kidney Foundation in collaboration with the US Food and Drug Administration and European Medicines Agency. Am J Kidney Dis. 2020;75(1):84–104. (PMID: 10.1053/j.ajkd.2019.06.009) Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Nowack C, et al. Design and baseline characteristics of the finerenone in reducing kidney failure and disease progression in diabetic kidney disease trial. Am J Nephrol. 2019;50(5):333–44. (PMID: 10.1159/000503713) Filippatos G, Anker SD, Agarwal R, Pitt B, Ruilope LM, Rossing P, et al. Finerenone and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes. Circulation. 2020. Goulooze B, Snelder N, Seelmann A, Horvat-Broecker A, Brinker M, Joseph A, Garmann D, Lippert J, Eissing T. Finerenone dose-exposure-serum potassium response analysis of FIDELIO-DKD phase 3: the role of dosing, titration, and inclusion criteria. Clin Pharmacokinet. 2022. https://doi.org/10.1007/s40262-021-01083-1 . (PMID: 10.1007/s40262-021-01083-134786651) van den Berg P, Ruppert M, Mesic E, Snelder N, Seelmann A, Heinig R, Joseph A, Garmann D, Lippert J, Eissing T. Finerenone dose-exposure-primary efficacy response in FIDELIO-DKD phase 3—population pharmacokinetic and time-to-event analysis. Clin Pharmacokinet. 2022. https://doi.org/10.1007/s40262-021-01082-2 . (PMID: 10.1007/s40262-021-01082-234773606) Vonesh E, Tighiouart H, Ying J, Heerspink HL, Lewis J, Staplin N, Inker L, Greene T. Mixed-effects models for slope-based endpoints in clinical trials of chronic kidney disease. Stat Med. 2019;38(22):4218–39. (PMID: 10.1002/sim.8282) Levey AS, Inker LA, Matsushita K, Greene T, Willis K, Lewis E, de Zeeuw D, Cheung AK, Coresh J. GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis. 2014;64(6):821–35. (PMID: 10.1053/j.ajkd.2014.07.030) Karlsson MO, Holford N. A tutorial on visual predictive checks. 2008;abstract 1434: p. 17. www.page-meeting.org/?abstract=1434 . Accessed 8 Apr 2022. Snelder N, Heinig R, Drenth HJ, Joseph A, Kolkhof P, Lippert J, et al. 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. Clin Pharmacokinet. 2020;59(3):359–70. (PMID: 10.1007/s40262-019-00820-x) Inker LA, Heerspink HJL, Tighiouart H, Levey AS, Coresh J, Gansevoort RT, et al. GFR slope as a surrogate end point for kidney disease progression in clinical trials: a meta-analysis of treatment effects of randomized controlled trials. J Am Soc Nephrol. 2019;30(9):1735–45. (PMID: 10.1681/ASN.2019010007) Weldegiorgis M, de Zeeuw D, Heerspink HJ. Renal end points in clinical trials of kidney disease. Curr Opin Nephrol Hypertens. 2015;24(3):284–9. (PMID: 25887898) Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med. 1982;307(11):652–9. (PMID: 10.1056/NEJM198209093071104) Holtkamp FA, de Zeeuw D, Thomas MC, Cooper ME, de Graeff PA, Hillege HJ, Parving HH, et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int. 2011;80(3):282–7. (PMID: 10.1038/ki.2011.79) Weir MR. Acute fall in glomerular filtration rate with renin-angiotensin system inhibition: a biomeasure of therapeutic success? Kidney Int. 2011;80(3):235–7. (PMID: 10.1038/ki.2011.132) Waijer SW, Gansevoort RT, Heerspink HJL. Change in albuminuria as a surrogate endpoint. Curr Opin Nephrol Hypertens. 2019;28(6):519–26. (PMID: 10.1097/MNH.0000000000000541) Heerspink HJL, Greene T, Tighiouart H, Gansevoort RT, Coresh J, Simon AL, et al. Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials. Lancet Diabetes Endocrinol. 2019;7(2):128–39. (PMID: 10.1016/S2213-8587(18)30314-0) de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004;65(6):2309–20. (PMID: 10.1111/j.1523-1755.2004.00653.x) Heerspink HJ, Ninomiya T, Persson F, Brenner BM, Brunel P, Chaturvedi N, et al. Is a reduction in albuminuria associated with renal and cardiovascular protection? A post hoc analysis of the ALTITUDE trial. Diabetes Obesity Metab. 2016;18(2):169–77. (PMID: 10.1111/dom.12600) Oshima M, Neuen BL, Li J, Perkovic V, Charytan DM, de Zeeuw D, et al. Early change in albuminuria with canagliflozin predicts kidney and cardiovascular outcomes: a post hoc analysis from the CREDENCE trial. J Am Soc Nephrol. 2020;31(12):2925–36. (PMID: 10.1681/ASN.2020050723) Jongs N, Greene T, Chertow GM, McMurray JJV, Langkilde AM, Correa-Rotter R, et al. Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9(11):755–66. (PMID: 10.1016/S2213-8587(21)00243-6) Persson F, Bain SC, Mosenzon O, Heerspink HJL, Mann JFE, Pratley R, et al. Changes in albuminuria predict cardiovascular and renal outcomes in type 2 diabetes: a post hoc analysis of the LEADER Trial. Diabetes Care. 2021;44(4):1020–6. (PMID: 10.2337/dc20-1622) Kolkhof P, Hartmann E, Freyberger A, Pavkovic M, Mathar I, Sandner P, et al. Effects of finerenone combined with empagliflozin in a model of hypertension-induced end-organ damage. Am J Nephrol. 2021;52(8):642–52. (PMID: 10.1159/000516213) Meraz-Muñoz AY, Weinstein J, Wald R. eGFR decline after SGLT2 inhibitor initiation: the tortoise and the hare reimagined. Kidney. 2021;360:1042–7. (PMID: 10.34067/KID.0001172021) |
المشرفين على المادة: | 0 (Mineralocorticoid Receptor Antagonists) 0 (Naphthyridines) 0 (Sodium-Glucose Transporter 2 Inhibitors) 0 (finerenone) |
تواريخ الأحداث: | Date Created: 20220504 Date Completed: 20220719 Latest Revision: 20240624 |
رمز التحديث: | 20240624 |
مُعرف محوري في PubMed: | PMC9287422 |
DOI: | 10.1007/s40262-022-01124-3 |
PMID: | 35508594 |
قاعدة البيانات: | MEDLINE |
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