Population pharmacokinetics of esaxerenone, a novel non-steroidal mineralocorticoid receptor blocker, in patients with essential hypertension, patients with diabetic nephropathy, and healthy volunteers.
Covariates
Diabetic nephropathy
Esaxerenone
Hypertension
Non-steroidal mineralocorticoid receptor blocker
Population pharmacokinetics
Journal
Drug metabolism and pharmacokinetics
ISSN: 1880-0920
Titre abrégé: Drug Metab Pharmacokinet
Pays: England
ID NLM: 101164773
Informations de publication
Date de publication:
Oct 2023
Oct 2023
Historique:
received:
06
02
2023
revised:
09
05
2023
accepted:
31
05
2023
medline:
25
9
2023
pubmed:
11
9
2023
entrez:
10
9
2023
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 37690271
pii: S1347-4367(23)00028-9
doi: 10.1016/j.dmpk.2023.100516
pii:
doi:
Substances chimiques
esaxerenone
N62TGJ04A1
Receptors, Mineralocorticoid
0
Itraconazole
304NUG5GF4
Rifampin
VJT6J7R4TR
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
100516Informations de copyright
Copyright © 2023 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest Kazutaka Yoshihara: Employee of Daiichi Sankyo Co., Ltd. Masato Fukae: Employee of Daiichi Sankyo Co., Ltd. Helen Kastrissios: Former employee of Certara Inc., which received consulting fees from Daiichi Sankyo Co., Ltd., and current employee of QuanTx Consulting. Russell Wada: Former employee of Certara Inc., which received consulting fees from Daiichi Sankyo Co., Ltd., and current chief executive officer of QuanTx Consulting. Takako Shimizu: Former employee of Daiichi Sankyo Co., Ltd, and current employee of OrphanPacific, Inc. Hitoshi Ishizuka: Employee of Daiichi Sankyo Co., Ltd.