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- Title
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.
- Authors
Snelder, Nelleke; Heinig, Roland; Drenth, Henk-Jan; Joseph, Amer; Kolkhof, Peter; Lippert, Jörg; Garmann, Dirk; Ploeger, Bart; Eissing, Thomas
- Abstract
<bold>Background: </bold>Finerenone (BAY 94-8862) is a potent non-steroidal, selective mineralocorticoid receptor antagonist being developed for the treatment of patients with type 2 diabetes and chronic kidney disease.<bold>Methods: </bold>We present the population pharmacokinetics and pharmacodynamics (PD) analysis for efficacy and safety markers based on data from two clinical phase IIb studies: ARTS-DN (NCT01874431) and ARTS-DN Japan (NCT01968668).<bold>Results: </bold>The pharmacokinetics of finerenone were adequately characterized, with estimated glomerular filtration rate (eGFR) and body weight as influencing covariates. The area under the plasma concentration-time curve in Japanese patients did not differ from that in the global population, and the investigated pharmacokinetics were dose- and time-linear. In addition, the pharmacokinetic model provided robust individual exposure estimates to study exposure-response. The concentration-effect relationship over time for the efficacy marker urinary albumin:creatinine ratio (UACR) was well-characterized by a maximum effect model indicating saturation at high exposures. For the safety markers, a log-linear model and a power model were identified for serum potassium concentration and eGFR, respectively, indicating attenuation of effect gains at high exposures. There was no apparent ethnic effect on the investigated pharmacokinetic-pharmacodynamic relationships. The model-predicted times to reach the full (99%) steady-state drug effect on UACR, serum potassium, and eGFR were 138, 20, and 85 days, respectively, while the pharmacokinetic half-life was 2-3 h and steady state was achieved after 2 days, indicating timescale separation.<bold>Conclusion: </bold>Our dose-exposure-response modeling and simulation indicates effects were largely saturated at finerenone 20 mg and doses of both 10 and 20 mg once daily appear safe and efficacious at reducing albuminuria.
- Subjects
CHRONIC kidney failure; TYPE 2 diabetes; PHARMACOLOGY; MINERALOCORTICOID receptors; GLOMERULAR filtration rate; BIOAVAILABILITY
- Publication
Clinical Pharmacokinetics, 2020, Vol 59, Issue 3, p359
- ISSN
0312-5963
- Publication type
journal article
- DOI
10.1007/s40262-019-00820-x