Dose–Exposure–Response Analysis of the Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone on UACR and eGFR: An Analysis from FIDELIO-DKD,Clinical Pharmacokinetics

当前位置： X-MOL 学术 › Clin. Pharmacokinet. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Dose–Exposure–Response Analysis of the Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone on UACR and eGFR: An Analysis from FIDELIO-DKD
Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2022-05-05 , DOI: 10.1007/s40262-022-01124-3
Sebastiaan Camiel Goulooze ₁ , Hiddo J L Heerspink ₂ , Martijn van Noort ₁ , Nelleke Snelder ₁ , Meike Brinker ₃ , Joerg Lippert ₄ , Thomas Eissing ₄

Affiliation

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.

中文翻译：

非类固醇盐皮质激素受体拮抗剂 Finerenone 对 UACR 和 eGFR 的剂量-暴露-反应分析：来自 FIDELIO-DKD 的分析

背景和目的

Finerenone 可降低慢性肾病和 2 型糖尿病患者肾衰竭的风险。尿白蛋白与肌酐比值 (UACR) 和估计肾小球滤过率 (eGFR) 的变化可以作为肾衰竭的替代指标。我们使用 FIDELIO-DKD 研究中的个体患者数据进行了剂量-暴露-反应分析，以确定在存在和不存在钠葡萄糖协同转运蛋白 2 抑制剂 (SGLT2is) 的情况下，finerenone 对这些替代物的影响。

方法

使用非线性混合效应群体药代动力学/药效学模型来量化标准护理期间 UACR 和 eGFR 方面的疾病进展以及在使用和不使用 SGLT2i 的情况下 Finerenone 的药效学影响。

结果

群体药代动力学/药效学模型充分描述了 Finerenone 暴露在随着时间的推移降低 UACR 和减缓 eGFR 下降方面的作用。 Finerenone 在第一年实现的 UACR 降低预示着其随后对减缓进行性 eGFR 下降的效果。 SGLT2i的使用并没有改变finerenone的效果。群体药代动力学/药效学模型以 97.5% 的置信度证明，根据 SGLT2i-finerenone 相互作用的 95% 置信区间（94.1），与未使用 SGLT2i 的患者相比，使用 SGLT2i 的患者在降低 UACR 方面，finerenone 的效果至少为 94.1%至 122%。 SGLT2i-finerenone 相互作用对 UACR 介导的慢性 eGFR 下降作用的 95% 置信区间为 9.5-144%。