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

• DOI: 10.1007/s40262-019-00820-x
• Publication Date: 2019-10-04T05:48:46Z
• Authors: Nelleke Snelder; Roland Heinig; Henk-Jan Drenth; Amer Joseph; Peter Kolkhof; Jörg Lippert; Dirk Garmann; Bart Ploeger; Thomas Eissing
• Keywords: Adult; Dose-Response Relationship, Drug; Body Weight; Middle Aged; Models, Theoretical; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Diabetes Mellitus, Type 2; Japan; Albumins; Area Under Curve; Creatinine; Potassium; Albuminuria; Humans; Original Research Article; Naphthyridines; Renal Insufficiency, Chronic; Safety; Aged; Glomerular Filtration Rate; Half-Life; Mineralocorticoid Receptor Antagonists

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.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).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.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.