Clinical pharmacokinetics · 2020
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.
Клиническое исследование II фазыСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Snelder Nelleke, Heinig Roland, Drenth Henk-Jan, Joseph Amer, Kolkhof Peter, Lippert Jörg, Garmann Dirk, Ploeger Bart, Eissing Thomas
Аннотация
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.
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.
Предметные рубрики MeSH
AdultAgedAlbuminsAlbuminuriaArea Under CurveBody WeightCreatinineDiabetes Mellitus, Type 2Dose-Response Relationship, DrugGlomerular Filtration RateHalf-LifeHumansJapanMiddle AgedMineralocorticoid Receptor AntagonistsModels, TheoreticalNaphthyridinesPotassiumRenal Insufficiency, ChronicSafetyTreatment Outcome