PMID- 31705436
OWN - NLM
STAT- MEDLINE
DCOM- 20200924
LR  - 20200924
IS  - 1865-8652 (Electronic)
IS  - 0741-238X (Print)
IS  - 0741-238X (Linking)
VI  - 37
IP  - 1
DP  - 2020 Jan
TI  - Pharmacokinetics and Safety of Single-Dose Esaxerenone in Japanese Subjects with 
      Mild to Moderate Hepatic Impairment.
PG  - 253-264
LID - 10.1007/s12325-019-01121-2 [doi]
AB  - INTRODUCTION: The mineralocorticoid receptor (MR) blocker esaxerenone is a new 
      treatment for hypertension in Japan and under development for treatment of 
      diabetic nephropathy. Hepatic impairment is known to impact the pharmacokinetics 
      (PKs) of other MR blocking drugs. The aim of the present study was to 
      characterise the PKs and safety of a single oral dose of esaxerenone in Japanese 
      subjects with mild-moderate hepatic impairment. METHODS: In this open-label, 
      parallel-group study, subjects with mild (Child-Pugh grade A) or moderate 
      (grade B) hepatic impairment, and healthy controls with normal hepatic function 
      matched by age and BMI (all groups n = 6), received a single 2.5-mg oral dose of 
      esaxerenone. Plasma concentrations were measured by liquid chromatography-tandem 
      mass spectrometry, and PK parameters were calculated using non-compartmental 
      analysis. RESULTS: Geometric least-squares mean (GLSM) ratios (90% confidence 
      intervals [CIs]) for area under the plasma concentration-time curve (up to the 
      last quantifiable time, up to infinity) in subjects with mild hepatic impairment 
      versus normal hepatic function were 0.837 (0.637, 1.099) and 0.824 (0.622, 
      1.092), respectively. Corresponding values for moderate hepatic impairment versus 
      normal hepatic function were 1.078 (0.820, 1.415) and 1.098 (0.829, 1.454). GLSM 
      ratios (90% CIs) for peak plasma concentration (C(max)) were 0.959 (0.778, 1.182) 
      for mild hepatic impairment versus normal hepatic function and 0.804 (0.653, 
      0.992) for moderate hepatic impairment versus normal hepatic function. Time to 
      C(max) and clearance values were comparable between groups. The incidence of 
      adverse events (AEs) was 16.7% in the moderate hepatic impairment and normal 
      hepatic function groups. One serious AE (hepatic encephalopathy) occurred in one 
      subject with moderate hepatic impairment. CONCLUSIONS: Mild to moderate hepatic 
      impairment had no clinically relevant effect on esaxerenone exposure. Esaxerenone 
      dosage adjustment based on PKs is unlikely to be needed in patients with mild to 
      moderate hepatic impairment. TRIAL REGISTRATION: JapicCTI-163339. FUNDING: 
      Daiichi Sankyo Co., Ltd.
FAU - Kurata, Akifumi
AU  - Kurata A
AUID- ORCID: 0000-0003-4667-6092
AD  - Daiichi Sankyo Co., Ltd., Tokyo, Japan. kurata.akifumi.vz@daiichisankyo.co.jp.
FAU - Yoshida, Takafumi
AU  - Yoshida T
AD  - Applied Bio-Pharmatech Kurume Clinical Pharmacology Clinic, Fukuoka, Japan.
FAU - Inoue, Megumi
AU  - Inoue M
AD  - SOUSEIKAI PS Clinic, Fukuoka, Japan.
FAU - Ishizuka, Tomoko
AU  - Ishizuka T
AD  - Daiichi Sankyo Co., Ltd., Tokyo, Japan.
FAU - Nakatsu, Takafumi
AU  - Nakatsu T
AD  - Daiichi Sankyo Co., Ltd., Tokyo, Japan.
FAU - Shimizu, Takako
AU  - Shimizu T
AD  - Daiichi Sankyo Co., Ltd., Tokyo, Japan.
FAU - Kato, Manabu
AU  - Kato M
AD  - Daiichi Sankyo Co., Ltd., Tokyo, Japan.
FAU - Nishikawa, Yasuhiro
AU  - Nishikawa Y
AD  - Daiichi Sankyo Co., Ltd., Tokyo, Japan.
FAU - Ishizuka, Hitoshi
AU  - Ishizuka H
AD  - Daiichi Sankyo Co., Ltd., Tokyo, Japan.
LA  - eng
SI  - JapicCTI/JapicCTI-163339
SI  - figshare/10.6084/m9.figshare.9929789
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191108
PL  - United States
TA  - Adv Ther
JT  - Advances in therapy
JID - 8611864
RN  - 0 (Mineralocorticoid Receptor Antagonists)
RN  - 0 (Pyrroles)
RN  - 0 (Sulfones)
RN  - N62TGJ04A1 (esaxerenone)
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Area Under Curve
MH  - Chromatography, High Pressure Liquid/methods
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Japan
MH  - Liver Diseases/*drug therapy/metabolism
MH  - Male
MH  - Middle Aged
MH  - Mineralocorticoid Receptor Antagonists/administration & dosage/*pharmacology
MH  - Pyrroles/administration & dosage/*pharmacokinetics
MH  - *Severity of Illness Index
MH  - Sulfones/administration & dosage/*pharmacokinetics
PMC - PMC6979450
OTO - NOTNLM
OT  - Esaxerenone
OT  - Hepatic impairment
OT  - Pharmacokinetics
OT  - Safety
EDAT- 2019/11/11 06:00
MHDA- 2020/09/25 06:00
PMCR- 2019/11/08
CRDT- 2019/11/10 06:00
PHST- 2019/08/23 00:00 [received]
PHST- 2019/11/11 06:00 [pubmed]
PHST- 2020/09/25 06:00 [medline]
PHST- 2019/11/10 06:00 [entrez]
PHST- 2019/11/08 00:00 [pmc-release]
AID - 10.1007/s12325-019-01121-2 [pii]
AID - 1121 [pii]
AID - 10.1007/s12325-019-01121-2 [doi]
PST - ppublish
SO  - Adv Ther. 2020 Jan;37(1):253-264. doi: 10.1007/s12325-019-01121-2. Epub 2019 Nov 
      8.