Abstract：
OBJECTIVE: To perform dose-exposure-response analyses to determine the effects of finerenone doses.
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.
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.
摘要：
目的：进行剂量-暴露-反应分析，以确定finerenone剂量的影响。
方法：两个随机，双盲,安慰剂对照3期试验招募来自全球站点的13026名2型糖尿病（T2D）随机参与者，每个估计的肾小球滤过率（eGFR）为25至90mL/min/1.73m2，尿白蛋白-肌酐比值（UACR）为30至5000mg/g，血清钾≤4.8mmol/L。干预措施是在标准护理的基础上，与安慰剂相比，滴定剂量的氟雷酮10或20mg。结果是血浆finerenone和血清钾浓度的轨迹，UACR,eGFR和肾脏综合结局，使用非线性混合效应群体药代动力学（PK）/药效学（PD）和参数时间至事件模型进行评估。
结果：对于钾，与10mg相比,较低的血清水平和较低的高钾血症发生率与较高剂量的finetenone20mg相关(p<0.001).PK/PD模型分析将这种观察到的逆关联与钾引导的剂量滴定相关联。用恒定的finenone剂量对假设的试验进行的模拟显示，暴露-钾反应关系浅但增加。同样，增加finenone暴露导致模拟的UACR减少小于剂量比例增加。模拟的UACR解释了95％的finerenone治疗效果减缓慢性eGFR下降。没有鉴定出不依赖UACR的finenerone效应。钠-葡萄糖协同转运蛋白-2(SGLT2)抑制剂和胰高血糖素样肽-1受体激动剂(GLP-1RA)治疗均未显著改变finetenone在降低UACR和eGFR下降中的作用。建模的eGFR解释了87%的finerenone对肾脏结局的治疗效果。没有发现eGFR非依赖性效应。
结论：这些分析提供了强有力的证据，证明了在控制血清钾升高中使用氟乐酮剂量滴定的有效性。UACR和eGFR可预测Finerenone治疗期间的肾脏结果。Finerenone的肾脏功效独立于同时使用SGLT2抑制剂和GLP-1RAs。
方法：两个随机，双盲,安慰剂对照3期试验招募来自全球站点的13026名2型糖尿病（T2D）随机参与者，每个估计的肾小球滤过率（eGFR）为25至90mL/min/1.73m2，尿白蛋白-肌酐比值（UACR）为30至5000mg/g，血清钾≤4.8mmol/L。干预措施是在标准护理的基础上，与安慰剂相比，滴定剂量的氟雷酮10或20mg。结果是血浆finerenone和血清钾浓度的轨迹，UACR,eGFR和肾脏综合结局，使用非线性混合效应群体药代动力学（PK）/药效学（PD）和参数时间至事件模型进行评估。
结果：对于钾，与10mg相比,较低的血清水平和较低的高钾血症发生率与较高剂量的finetenone20mg相关(p<0.001).PK/PD模型分析将这种观察到的逆关联与钾引导的剂量滴定相关联。用恒定的finenone剂量对假设的试验进行的模拟显示，暴露-钾反应关系浅但增加。同样，增加finenone暴露导致模拟的UACR减少小于剂量比例增加。模拟的UACR解释了95％的finerenone治疗效果减缓慢性eGFR下降。没有鉴定出不依赖UACR的finenerone效应。钠-葡萄糖协同转运蛋白-2(SGLT2)抑制剂和胰高血糖素样肽-1受体激动剂(GLP-1RA)治疗均未显著改变finetenone在降低UACR和eGFR下降中的作用。建模的eGFR解释了87%的finerenone对肾脏结局的治疗效果。没有发现eGFR非依赖性效应。
结论：这些分析提供了强有力的证据，证明了在控制血清钾升高中使用氟乐酮剂量滴定的有效性。UACR和eGFR可预测Finerenone治疗期间的肾脏结果。Finerenone的肾脏功效独立于同时使用SGLT2抑制剂和GLP-1RAs。
