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

Abstract

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 diabetesmellitus. 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. 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 10mg tablet (n = 10 and n = 11, respectively). 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 (1.25-20mg), 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 20mg with a high-fat, high-calorie meal, AUC∞ increased (+21%), Cmax decreased (-19%), and tmax was prolonged (2.47vs. 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%). 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.