健康受试者和核苷(t)ide逆转录酶抑制剂抑制的慢性乙型肝炎患者的EDP-514

IF 1.3 4区 医学 Q4 INFECTIOUS DISEASES
Jordan J Feld, Eric Lawitz, Tuan Nguyen, Jacob Lalezari, Tarek Hassanein, Paul Martin, Steven-Huy Han, Douglas Dieterich, Jeanne-Marie Giard, Guy De La Rosa, Alaa Ahmad, Ed Luo, Annie L Conery, Nathalie Adda
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引用次数: 4

摘要

背景:慢性乙型肝炎(CHB)仍然是发病率和死亡率的主要原因。EDP-514是一种有效的乙型肝炎病毒(HBV)核心抑制剂,可降低HBV感染嵌合小鼠的病毒载量。这项首次人体研究评估了健康人体内EDP-514的安全性、耐受性和药代动力学(PK)以及慢性乙型肝炎患者的抗病毒活性。方法:在第一部分中,82名受试者在进食或禁食状态下接受安慰剂或EDP-514,单次递增剂量50-800 mg,多次递增剂量200-800 mg,持续14天。在第2部分中,24例HBV dna抑制、核苷(NUC)治疗(即NUC抑制)的CHB患者接受EDP-514 200-800 mg或安慰剂治疗28天。结果:EDP-514在健康受试者和慢性乙型肝炎患者中耐受性良好,不良事件以轻度为主。在第1部分中,EDP-514暴露量以大约剂量正比的方式增加,单次给药后可达600 mg, 14天给药后可达400 mg。在第2部分中,EDP-514暴露在第1天和第28天随剂量线性增加,第28天有一些积累,中位波谷浓度(Ctrough)约为剂量范围内蛋白质调节的50%有效浓度(EC50)的20倍。在200 mg、400 mg、800 mg和安慰剂组,HBV RNA从基线到第28天的平均变化分别为-2.03、-1.67、-1.87和-0.58 log U/mL。结论:EDP-514具有良好的耐受性,具有支持每日一次给药的PK谱,并且降低了nucc抑制的CHB患者的HBV RNA水平。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
EDP-514 in healthy subjects and nucleos(t)ide reverse transcriptase inhibitor-suppressed patients with chronic hepatitis B.

Background: Chronic hepatitis B (CHB) remains a major cause of morbidity and mortality. EDP-514 is a potent core inhibitor of hepatitis B virus (HBV) that reduces viral load reduction in HBV-infected chimeric mice. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics (PK) of EDP-514 in healthy subjects and antiviral activity in patients with CHB.

Methods: In Part 1, 82 subjects received placebo or EDP-514 in fed or fasted state as single ascending doses of 50-800 mg and multiple ascending doses of 200-800 mg for 14 days. In Part 2, 24 HBV DNA-suppressed, nucleos(t)ide (NUC)-treated (i.e., NUC-suppressed) CHB patients received EDP-514 200-800 mg or placebo for 28 days.

Results: EDP-514 was well tolerated in healthy subjects and CHB patients with most adverse events of mild intensity. In Part 1, EDP-514 exposure increased in an approximately dose proportional manner up to 600 mg after single doses and up to 400 mg after 14-day dosing. In Part 2, EDP-514 exposure increased linearly with dose on Day 1 and Day 28, with some accumulation for Day 28 and median trough concentrations (Ctrough) approximately 20-fold above the protein-adjusted 50% effective concentration (EC50) for the dose range. Mean change in HBV RNA from baseline to Day 28 was -2.03, -1.67, -1.87, and -0.58 log U/mL in the 200 mg, 400 mg, 800 mg, and placebo CHB groups, respectively.

Conclusions: EDP-514 was well tolerated, had a PK profile supporting once daily dosing, and reduced HBV RNA levels in NUC-suppressed CHB patients.

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来源期刊
Antiviral Therapy
Antiviral Therapy 医学-病毒学
CiteScore
2.60
自引率
8.30%
发文量
35
审稿时长
4-8 weeks
期刊介绍: Antiviral Therapy (an official publication of the International Society of Antiviral Research) is an international, peer-reviewed journal devoted to publishing articles on the clinical development and use of antiviral agents and vaccines, and the treatment of all viral diseases. Antiviral Therapy is one of the leading journals in virology and infectious diseases. The journal is comprehensive, and publishes articles concerning all clinical aspects of antiviral therapy. It features editorials, original research papers, specially commissioned review articles, letters and book reviews. The journal is aimed at physicians and specialists interested in clinical and basic research.
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