Finerenone Dose-Exposure-Response for the Primary Kidney Outcome in FIDELIO-DKD Phase III: Population Pharmacokinetic and Time-to-Event Analysis

• DOI: 10.1007/s40262-021-01082-2
• Publication Date: 2021-11-13T06:02:45Z
• Authors: Paul van den Berg; Martijn Ruppert; Emir Mesic; Nelleke Snelder; Andreas Seelmann; Roland Heinig; Amer Joseph; Dirk Garmann; Joerg Lippert; Thomas Eissing
• Keywords: Male; 03 medical and health sciences; 0302 clinical medicine; Diabetes Mellitus, Type 2; Humans; Female; Original Research Article; Naphthyridines; Renal Insufficiency, Chronic; Kidney; 3. Good health

Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist that recently demonstrated efficacy in delaying chronic kidney disease progression and reducing cardiovascular events patients with type 2 diabetes FIDELIO-DKD, where 5734 were randomized 1:1 to receive either titrated finerenone doses of 10 or 20 mg once daily placebo, median follow-up 2.6 years. Nonlinear mixed-effects population pharmacokinetic models used analyze the pharmacokinetics sparsely sampled all subjects receiving finerenone. Post-hoc model parameter estimates together dosing histories allowed computation individual exposures subsequent parametric time-to-event analyses primary outcome. The adequately captured typical its variability. Either covariate effects multivariate forward-simulations subgroups interest contained within equivalence range 80–125% around exposure. exposure-response relationship was characterized by maximum effect estimating low half-maximal concentration at 0.166 µg/L maximal hazard decrease 36.1%. Prognostic factors for treatment-independent risk included estimated glomerular filtration rate high urine-to-creatinine ratio increasing risk, while concomitant sodium-glucose transport protein inhibitor use decreased risk. Importantly, no co-medication-related modification treatment per se could be identified. None tested covariates had clinical relevance FIDELIO-DKD. on outcomes approached saturation towards provided additive benefits.