Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone (BAY 94-8862) in Individuals with Mild or Moderate Hepatic Impairment
Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone (BAY 94-8862) in Individuals with Mild or Moderate Hepatic Impairment
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DOI：
10.1007/s13318-019-00547-x
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发表时间：
2019-10-01
影响因子：
1.9
通讯作者：
Halabi, Atef
中科院分区：
文献类型：
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作者：
Heinig, Roland;Lambelet, Marc;Halabi, Atef
背景与目的：菲诺酮(BAY 94-8862)是一种选择性的非甾体类盐皮质激素受体拮抗剂。本研究的目的是评估轻度或中度肝损害对非那瑞酮的药代动力学、安全性和耐受性的影响。方法采用单中心、非随机、非对照、非盲法、分组分层的观察设计。对轻度或中度肝损伤的参与者(Child-Pugh A评分5-6分[n=9]或Child-Pugh B评分7-9分[n=9])以及年龄、体重和性别匹配的健康参与者(n=9)，单剂量口服5 mg非那瑞酮作为片剂。评价非那瑞酮及其代谢物在血浆和尿液中的药代动力学，并监测其安全性和耐受性。结果中度肝损害患者血浆浓度-时间曲线下面积(AUC)和游离AUC分别比正常对照组增加38%和55%，而最大血药浓度(C-max)无明显变化。在轻度肝损害的参与者中，没有看到对AUC或C-max的明显影响。非勒酮在所有参与者中都是安全的，耐受性良好。结论轻、中度肝损伤对非那瑞酮全身暴露的影响较小，与其肝脏出血量低、胃肠道优先于肝脏首过清除相一致。考虑到AUC的小幅增加和C-max的无变化，对于轻度或中度肝损害的患者，似乎没有必要进行剂量适应。
Background and Objectives Finerenone (BAY 94-8862) is a selective, nonsteroidal mineralocorticoid receptor antagonist. The aim of this study was to assess the effect of mild or moderate hepatic impairment on the pharmacokinetics, safety and tolerability of finerenone. Methods The study was conducted in a single-center, nonrandomized, noncontrolled, nonblinded observational design with group stratification. A single oral 5-mg dose of finerenone was administered as a tablet to participants with mild or moderate hepatic impairment (Child-Pugh A, score 5-6 [n = 9], or Child-Pugh B, score 7-9 [n = 9], respectively) and to age-, weight- and sex-matched healthy participants (n = 9). The pharmacokinetics of finerenone and its metabolites were assessed in plasma and urine, and safety and tolerability were monitored. Results Finerenone area under the plasma concentration-time curve (AUC) and unbound AUC were 38% and 55% greater, respectively, in participants with moderate hepatic impairment than in healthy participants, whereas maximum plasma concentration (C-max) was unchanged. No clear effects on AUC or C-max were seen in participants with mild hepatic impairment. Finerenone was safe and well tolerated in all participants. Conclusion The effects of mild or moderate hepatic impairment on systemic exposure of finerenone are small, consistent with its low hepatic extraction and preponderance of gastrointestinal over hepatic first-pass clearance. Considering the small increases in AUC and the absence of changes in C-max, a dose adaptation does not appear to be warranted in patients with mild or moderate hepatic impairment.