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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
- Source :
- Clinical Pharmacokinetics
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- Background 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. Methods 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). Results 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. Conclusion 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. Electronic supplementary material The online version of this article (10.1007/s40262-019-00820-x) contains supplementary material, which is available to authorized users.
- Subjects :
- Adult
Finerenone
Population
030232 urology & nephrology
Renal function
030204 cardiovascular system & hematology
Pharmacology
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Japan
Pharmacokinetics
Albumins
medicine
Albuminuria
Humans
Pharmacology (medical)
Original Research Article
Naphthyridines
Renal Insufficiency, Chronic
education
Aged
Mineralocorticoid Receptor Antagonists
Creatinine
education.field_of_study
Dose-Response Relationship, Drug
business.industry
Body Weight
Middle Aged
Models, Theoretical
medicine.disease
Treatment Outcome
Diabetes Mellitus, Type 2
chemistry
Area Under Curve
Pharmacodynamics
Potassium
Safety
medicine.symptom
business
Glomerular Filtration Rate
Half-Life
Kidney disease
Subjects
Details
- ISSN :
- 11791926 and 03125963
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- Clinical Pharmacokinetics
- Accession number :
- edsair.doi.dedup.....f6c9208a9f324acf3ed71c94f0fdaccf