Published in:
Open Access
01-01-2020 | Hepatic Encephalopathy | Original Research
Pharmacokinetics and Safety of Single-Dose Esaxerenone in Japanese Subjects with Mild to Moderate Hepatic Impairment
Authors:
Akifumi Kurata, Takafumi Yoshida, Megumi Inoue, Tomoko Ishizuka, Takafumi Nakatsu, Takako Shimizu, Manabu Kato, Yasuhiro Nishikawa, Hitoshi Ishizuka
Published in:
Advances in Therapy
|
Issue 1/2020
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Abstract
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 (Cmax) 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 Cmax 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.