Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

13.2 Pharmacodynamics
In FIDELIO-DKD and FIGARO-DKD, randomized, double-blind, placebo-controlled, multicenter studies in adult patients with chronic kidney disease associated with type 2 diabetes, the placebo-corrected relative reduction in urinary albumin-to-creatinine ratio (UACR) in patients randomized to finerenone was 31% (95% CI 29-34%) and 32% (95% CI 30-35%) respectively at Month 4 and remained stable for the duration of the trial.
In ARTS DN, a randomized, double-blind, placebo-controlled, multicenter phase IIb dose finding study in adults with CKD and T2D, the placebo-corrected relative reduction in UACR at Day 90 was 25% and 38% in patients treated with finerenone 10 mg and 20 mg once daily, respectively.
In patients treated with Kerendia, the mean systolic blood pressure decreased by 3 mmHg and the mean diastolic blood pressure decreased by 1-2 mmHg at month 1, remaining stable thereafter.
Cardiac Electrophysiology
At a dose 4 times the maximum approved recommended dose, finerenone does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetic Properties

13.3 Pharmacokinetics
Finerenone exposure increased proportionally over a dose range of 1.25 to 80 mg (0.06 to 4 times the maximum approved recommended dosage). Steady state of finerenone was achieved after 2 days of dosing. The estimated steady-state geometric mean Cmax,md was 160 µg/L and steady-state geometric mean AUCτ,md was 686 µg.h/L following administration of finerenone 20 mg to patients.


Absorption
Finerenone is completely absorbed after oral administration but undergoes metabolism resulting in absolute bioavailability of 44%. Finerenone Cmax was achieved between 0.5 and 1.25 hours after dosing.
Effect of Food
There was no clinically significant effect on finerenone AUC following administration with high fat, high calorie food.
Distribution
The volume of distribution at steady-state (Vss) of finerenone is 52.6 L. Plasma protein binding of finerenone is 92%, primarily to serum albumin, in vitro.
Elimination
The terminal half-life of finerenone is about 2 to 3 hours, and the systemic blood clearance is about 25 L/h.
Metabolism
Finerenone is primarily metabolized by CYP3A4 (90%) and to a lesser extent by CYP2C8 (10%) to inactive metabolites.
Excretion
About 80% of the administered dose is excreted in urine (<1% as unchanged) and approximately 20% in feces (< 0.2% as unchanged).
Specific Populations
There are no clinically significant effects of age (18 to 79 years), sex, race/ethnicity (White, Asian, Black, and Hispanic), or weight (58 to 121 kg) on the pharmacokinetics of finerenone.
Renal Impairment
There were no clinically relevant differences in finerenone AUC or Cmax values in patients with eGFR 15 to < 90 mL/min/1.73m2 compared to eGFR ≥ 90 mL/min/1.73 m2. For dosing recommendations based on eGFR and serum potassium levels see Dosage and Administration (5).
Hepatic Impairment
There was no clinically significant effect on finerenone exposure in cirrhotic patients with mild hepatic impairment (Child Pugh A).
Finerenone mean AUC was increased by 38% and Cmax was unchanged in cirrhotic patients with moderate hepatic impairment (Child Pugh B) compared to healthy control subjects.
The effect of severe hepatic impairment (Child Pugh C) on finerenone exposure was not studied.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Strong CYP3A Inhibitors: Concomitant use of itraconazole (strong CYP3A4 inhibitor) increased finerenone AUC by >400%.
Moderate CYP3A Inhibitors: Concomitant use of erythromycin (moderate CYP3A4 inhibitor) increased finerenone mean AUC and Cmax by 248% and 88%, respectively.

Weak CYP3A Inhibitors: Concomitant use of amiodarone (weak CYP3A4 inhibitor) increased finerenone AUC by 21%.

Strong or Moderate CYP3A Inducers: Concomitant use of efavirenz (moderate CYP3A4 inducer) and rifampicin (strong CYP3A4 inducer) decreased finerenone AUC by 80% and 90%, respectively.


Other Drugs: There was no clinically significant difference in finerenone pharmacokinetics when used concomitantly with gemfibrozil (strong CYP2C8 inhibitor), omeprazole (proton pump inhibitor), or an aluminium hydroxide and magnesium hydroxide antacid. There were no clinically significant pharmacokinetic differences for either finerenone or concomitant digoxin (P-gp substrate) or warfarin (CYP2C9 substrate). There were no clinically significant differences in the pharmacokinetics of either midazolam (CYP3A4 substrate) or repaglinide (CYP2C8 substrate) when used concomitantly with finerenone. Multiple doses of 40 mg finerenone once-daily had no clinically relevant effect on AUC or Cmax of the BCRP and OATP substrate rosuvastatin.