European journal of drug metabolism and pharmacokinetics · 2022
Results From Phase I Studies Investigating the Dose Linearity of Finerenone Tablets and the Influence of Food or pH-Modifying Comedications on its Pharmacokinetics in Healthy Male Volunteers.
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Heinig Roland, Nagelschmitz Johannes, Loewen Stephanie
Аннотация
BACKGROUND AND OBJECTIVES: Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that reduces the risk of adverse kidney and cardiovascular outcomes in patients with chronic kidney disease associated with type 2 diabetes mellitus. Clinical phase I studies with finerenone were carried out to assess its pharmacokinetics and the influence of common covariables on its absorption after oral administration.
METHODS: Three crossover studies in healthy male volunteers with single-dose administration of finerenone investigated the dose linearity of a film-coated tablet (1.25-10 mg [n = 24] and 10-20 mg [n = 18]), the effect of food on the 20 mg tablet (n = 18), and the effects of the proton-pump inhibitor omeprazole (4 days pre-treatment and co-administration 2 h before finerenone) and an aluminum/magnesium hydroxide-containing antacid (10 mL [Maalox®] 70 mVal, simultaneous intake) on the 10 mg tablet (n = 10 and n = 11, respectively).
RESULTS: Finerenone was rapidly absorbed (time to reach maximum plasma concentration [tmax] was 0.50-0.75 h). Area under the curve from zero to infinity (AUC∞) and the maximum concentration (Cmax) increased in proportion to dose in the range investigated in clinical phase II and phase III studies (1.25-20 mg), with point estimates for the ratio of dose-normalized AUC∞ and Cmax (20 mg/10 mg, approved therapeutic doses) of 0.9943 and 0.9301. After the administration of finerenone 20 mg with a high-fat, high-calorie meal, AUC∞ increased (+ 21%), Cmax decreased (-19%), and tmax was prolonged (2.47 vs. 0.75 h) when compared with the fasting state. Omeprazole had no effect on finerenone AUC∞ and Cmax. Maalox had no effect on finerenone AUC∞ and led to a non-clinically-relevant decrease in Cmax (-19%).
CONCLUSIONS: The pharmacokinetics of the finerenone film-coated tablet were linear. High-fat, high-calorie food had no clinically relevant effect on the pharmacokinetics of finerenone. In addition, pH-modifying comedications were not found to alter the pharmacokinetics of finerenone and were deemed safe for co-administration.
METHODS: Three crossover studies in healthy male volunteers with single-dose administration of finerenone investigated the dose linearity of a film-coated tablet (1.25-10 mg [n = 24] and 10-20 mg [n = 18]), the effect of food on the 20 mg tablet (n = 18), and the effects of the proton-pump inhibitor omeprazole (4 days pre-treatment and co-administration 2 h before finerenone) and an aluminum/magnesium hydroxide-containing antacid (10 mL [Maalox®] 70 mVal, simultaneous intake) on the 10 mg tablet (n = 10 and n = 11, respectively).
RESULTS: Finerenone was rapidly absorbed (time to reach maximum plasma concentration [tmax] was 0.50-0.75 h). Area under the curve from zero to infinity (AUC∞) and the maximum concentration (Cmax) increased in proportion to dose in the range investigated in clinical phase II and phase III studies (1.25-20 mg), with point estimates for the ratio of dose-normalized AUC∞ and Cmax (20 mg/10 mg, approved therapeutic doses) of 0.9943 and 0.9301. After the administration of finerenone 20 mg with a high-fat, high-calorie meal, AUC∞ increased (+ 21%), Cmax decreased (-19%), and tmax was prolonged (2.47 vs. 0.75 h) when compared with the fasting state. Omeprazole had no effect on finerenone AUC∞ and Cmax. Maalox had no effect on finerenone AUC∞ and led to a non-clinically-relevant decrease in Cmax (-19%).
CONCLUSIONS: The pharmacokinetics of the finerenone film-coated tablet were linear. High-fat, high-calorie food had no clinically relevant effect on the pharmacokinetics of finerenone. In addition, pH-modifying comedications were not found to alter the pharmacokinetics of finerenone and were deemed safe for co-administration.