Pharmacokinetics and Safety of Fenofibrate in Participants with Mild Hepatic Impairment or with Advanced Fibrosis due to Metabolic-Associated Fatty Liver Disease.

IF 2.9 4区 医学
Islam R Younis, Elijah J Weber, Cara Nelson, Ann R Qin, Timothy R Watkins, Ahmed A Othman
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引用次数: 0

Abstract

Fenofibrate is contraindicated in patients with advanced hepatic fibrosis due to limited clinical data. We evaluated the pharmacokinetics and safety of fenofibrate in participants with mild hepatic impairment (phase 1 study) or advanced fibrosis due to metabolic-associated fatty liver disease (MAFLD; phase 2a study). In the phase 1 study, participants with mild hepatic impairment and healthy matched controls (each n = 10) received a single, oral dose of fenofibrate 48 mg. In the phase 2a study, participants with hypertriglyceridemia and advanced fibrosis due to MAFLD were randomly assigned (1:1) fenofibrate 48 mg (n = 15) or fenofibrate 145 mg (n = 16) combined with firsocostat 20 mg, taken orally once daily for 24 weeks. Pharmacokinetics and safety were assessed in both studies. In the phase 1 study, the AUCinf of fenofibric acid was 25% higher in participants with mild hepatic impairment than in healthy matched participants. In the phase 2a study, the AUCss,0-24 of fenofibric acid (fenofibrate 48 mg dose) in participants with F3 fibrosis and F4 cirrhosis was approximately 60% and 80%, respectively, higher than the AUCinf in healthy participants in the phase 1 study, and was 20% higher in participants with F4 cirrhosis than in participants with F3 fibrosis. In both studies, most adverse events and laboratory abnormalities were grade 1-2. In the phase 2a study, three participants had grade 3 hypertriglyceridemia. Fenofibrate was well tolerated, and modest differences were observed in fenofibric acid exposure in participants with mild hepatic impairment or advanced fibrosis due to MAFLD.

非诺贝特在代谢性脂肪肝引起的轻度肝功能损害或晚期纤维化患者中的药代动力学和安全性
由于临床资料有限,非诺贝特是晚期肝纤维化患者的禁忌症。我们评估了非诺贝特在因代谢性脂肪性肝病(MAFLD;第2a期研究)。在1期研究中,轻度肝功能损害的参与者和健康匹配的对照组(每个n = 10)接受单次口服剂量48 mg的非诺贝特。在2a期研究中,由于MAFLD导致的高甘油三酯血症和晚期纤维化的参与者被随机分配(1:1)非诺贝特48 mg (n = 15)或非诺贝特145 mg (n = 16)联合firsocostat 20 mg,每天口服一次,持续24周。两项研究均评估了药代动力学和安全性。在1期研究中,轻度肝功能损害的受试者中,非诺纤维酸的AUCinf比健康匹配的受试者高25%。在2a期研究中,非诺贝特(非诺贝特48 mg剂量)在F3型纤维化和F4型肝硬化参与者中的auss,0-24分别约为60%和80%,高于1期研究中auinf健康参与者,F4型肝硬化参与者比F3型纤维化参与者高20%。在这两项研究中,大多数不良事件和实验室异常都是1-2级。在2a期研究中,3名参与者患有3级高甘油三酯血症。非诺贝特耐受性良好,并且在因MAFLD引起的轻度肝功能损害或晚期纤维化的参与者中观察到非诺贝特酸暴露的适度差异。
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来源期刊
Journal of Clinical Pharmacology
Journal of Clinical Pharmacology PHARMACOLOGY & PHARMACY-
自引率
3.40%
发文量
0
期刊介绍: The Journal of Clinical Pharmacology (JCP) is a Human Pharmacology journal designed to provide physicians, pharmacists, research scientists, regulatory scientists, drug developers and academic colleagues a forum to present research in all aspects of Clinical Pharmacology. This includes original research in pharmacokinetics, pharmacogenetics/pharmacogenomics, pharmacometrics, physiologic based pharmacokinetic modeling, drug interactions, therapeutic drug monitoring, regulatory sciences (including unique methods of data analysis), special population studies, drug development, pharmacovigilance, womens’ health, pediatric pharmacology, and pharmacodynamics. Additionally, JCP publishes review articles, commentaries and educational manuscripts. The Journal also serves as an instrument to disseminate Public Policy statements from the American College of Clinical Pharmacology.
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