Population pharmacokinetics of esaxerenone, a novel non-steroidal mineralocorticoid receptor blocker, in patients with essential hypertension, patients with diabetic nephropathy, and healthy volunteers.

Abstract

OBJECTIVES:

Esaxerenone is a novel, non-steroidal mineralocorticoid receptor (MR) blocker with improved selectivity and affinity for MR. The objectives of this study were to model the population pharmacokinetics of esaxerenone in a diverse population and to evaluate the effect of covariates on pharmacokinetics parameters.

METHODS:

A total of 8263 plasma esaxerenone concentrations from 166 healthy volunteers, 1097 hypertensive patients and 360 patients with diabetic nephropathy were pooled. A three-compartment model with sequential zero- and first-order absorption was used to describe the time-courses of plasma esaxerenone following single and multiple doses once daily for up to 12 weeks. Covariate effects were estimated using the full covariate modeling approach. Clinical relevance of covariates was ascertained using tornado plots.

RESULTS:

Esaxerenone was estimated to have high bioavailability (85.3%), low clearance (3.28 L/h) and relatively large distribution volume at steady state (94.8 L). Body weight (-26 to +36%) and coadministration of itraconazole (+64%) or rifampicin (-68%) were associated with a greater influence on esaxerenone exposure.

CONCLUSIONS:

The most influential covariates on esaxerenone exposure were coadministrations of itraconazole and rifampicin, followed by body weight. The clinical relevance of effects of renal impairment, mild to moderate hepatic impairment, and age is limited.

• Authors: Kazutaka Yoshihara, Masato Fukae, Helen Kastrissios, Russell Wada, Takako Shimizu, Hitoshi Ishizuka
• Journal: Drug metabolism and pharmacokinetics (Drug Metab Pharmacokinet) Vol. 52 Pg. 100516 (Oct 2023) ISSN: 1880-0920 [Electronic] England
• PMID: 37690271 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Chemical References

• esaxerenone
• Receptors, Mineralocorticoid
• Itraconazole
• Rifampin

Topics

• Humans
• Diabetic Nephropathies (drug therapy)
• Receptors, Mineralocorticoid
• Healthy Volunteers
• Itraconazole
• Rifampin
• Essential Hypertension
• Body Weight
• Diabetes Mellitus