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- Title
Finerenone Dose-Exposure-Response for the Primary Kidney Outcome in FIDELIO-DKD Phase III: Population Pharmacokinetic and Time-to-Event Analysis.
- Authors
van den Berg, Paul; Ruppert, Martijn; Mesic, Emir; Snelder, Nelleke; Seelmann, Andreas; Heinig, Roland; Joseph, Amer; Garmann, Dirk; Lippert, Joerg; Eissing, Thomas
- Abstract
Background: Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist that recently demonstrated efficacy in delaying chronic kidney disease progression and reducing cardiovascular events in patients with chronic kidney disease and type 2 diabetes in FIDELIO-DKD, where 5734 patients were randomized 1:1 to receive either titrated finerenone doses of 10 or 20 mg once daily or placebo, with a median follow-up of 2.6 years. Methods: Nonlinear mixed-effects population pharmacokinetic models were used to analyze the pharmacokinetics in FIDELIO-DKD, sparsely sampled in all subjects receiving finerenone. Post-hoc model parameter estimates together with dosing histories allowed the computation of individual exposures used in subsequent parametric time-to-event analyses of the primary kidney outcome. Results: The population pharmacokinetic model adequately captured the typical pharmacokinetics of finerenone and its variability. Either covariate effects or multivariate forward-simulations in subgroups of interest were contained within the equivalence range of 80–125% around typical exposure. The exposure-response relationship was characterized by a maximum effect model estimating a low half-maximal effect concentration at 0.166 µg/L and a maximal hazard decrease at 36.1%. Prognostic factors for the treatment-independent chronic kidney disease progression risk included a low estimated glomerular filtration rate and a high urine-to-creatinine ratio increasing the risk, while concomitant sodium-glucose transport protein 2 inhibitor use decreased the risk. Importantly, no sodium-glucose transport protein 2 inhibitor co-medication-related modification of the finerenone treatment effect per se could be identified. Conclusions: None of the tested pharmacokinetic covariates had clinical relevance in FIDELIO-DKD. Finerenone effects on kidney outcomes approached saturation towards 20 mg once daily and sodium-glucose transport protein 2 inhibitor use provided additive benefits.
- Subjects
CARRIER proteins; CHRONIC kidney failure; PROGNOSIS; PROTEIN transport; DISEASE risk factors; GLUCOSE transporters
- Publication
Clinical Pharmacokinetics, 2022, Vol 61, Issue 3, p439
- ISSN
0312-5963
- Publication type
Article
- DOI
10.1007/s40262-021-01082-2