Development of an oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 open-label dose-escalation safety trial and pharmacokinetic analysis in healthy Kenyan adults.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-03-01 Epub Date: 2025-02-27 DOI:10.1016/j.ebiom.2025.105600

Michael Abouyannis, Yvonne K Nyambura, Samson Ngome, Debra Riako, Jennifer Musyoki, Charles Muiruri, Benedict Orindi, Laura Else, Alieu Amara, Laura Dickinson, Rachel H Clare, Laura-Oana Albulescu, Adam P Westhorpe, Jeroen Kool, Ifedayo Adetifa, Francis M Ndungu, Richard FitzGerald, Saye Khoo, David G Lalloo, Nicholas R Casewell, Mainga Hamaluba

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引用次数: 0

Abstract

Background: Viperidae snakes are responsible for many of the 94,000 deaths caused by snakebite envenoming each year. The most pathological venom component of this globally diverse family of snakes are the zinc-dependent snake venom metalloproteinase (SVMP) enzymes, which can be inhibited by the metal chelator, unithiol. A short-course oral regimen, readily available and rapidly deployed ahead of hospital admission is needed.

Methods: This open-label, phase 1 clinical trial assessed the safety of single ascending oral, multiple ascending oral, and single ascending intravenous doses of unithiol in 64 healthy adult volunteers from Kilifi County, Kenya. The multiple dose stage was informed by an interim safety and pharmacokinetic analysis, and predefined target plasma concentrations. Plasma concentrations of unithiol were measured using high-performance liquid chromatography-mass spectrometry, and safety was described by full adverse event reporting.

Findings: 175 individuals were screened, and 64 (median age 30 years, IQR 25-38 years) received the study drug. There were no dose limiting toxicities or serious adverse events. There were 61 solicited adverse events, 17 related unsolicited adverse events, and 53 laboratory adverse events, all of mild or moderate severity. The maximum oral dose of 1500 mg was well tolerated and associated with the following pharmacokinetic parameters: C_max 14.7 μg/mL, T_max 2.9 h, T_1/2 18.4 h, and AUC_0-∞ 204.5 μg.h/mL.

Interpretation: The phase 2 recommended dose (1500 mg loading dose, followed by 900 mg doses at 6-h and 24-h) has no safety concerns, and has promising pharmacokinetic properties for clinical use. Unithiol is affordable, stable at room temperature, and has the potential to be given orally in remote rural clinics. Its further development for snakebite indication is warranted.

Funding: Wellcome Trust, Bloomsbury Set, and Cures Within Reach.

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背景：在每年因被蛇咬伤而死亡的 94,000 人中，许多人是由蝰科蛇造成的。这一全球性蛇类家族中最具病理特征的毒液成分是依赖锌的蛇毒金属蛋白酶（SVMP），金属螯合剂 unithiol 可抑制这种酶。我们需要一种可在入院前迅速使用的短程口服疗法：这项开放标签的 1 期临床试验评估了单次递增口服、多次递增口服和单次递增静脉注射 unithiol 对肯尼亚基利菲县 64 名健康成年志愿者的安全性。多剂量阶段是根据中期安全性和药代动力学分析以及预先确定的目标血浆浓度确定的。使用高效液相色谱-质谱法测量血浆中 unithiol 的浓度，并通过完整的不良事件报告来描述安全性：共筛选出 175 人，其中 64 人（中位年龄 30 岁，IQR 25-38 岁）接受了研究药物。没有出现限制剂量的毒性反应或严重不良事件。61例主动报告的不良事件、17例相关的主动报告的不良事件和53例实验室不良事件均为轻度或中度。最大口服剂量为 1500 毫克的耐受性良好，药代动力学参数如下：Cmax 14.7 μg/mL，Tmax 2.9 h，T1/2 18.4 h，AUC0-∞ 204.5 μg.h/mL：第二阶段推荐剂量（1500 毫克负荷剂量，随后在 6 小时和 24 小时各服用 900 毫克剂量）不存在安全性问题，其药代动力学特性有望用于临床。Unithiol 价格低廉，室温下稳定，可在偏远农村诊所口服。它在蛇咬伤适应症方面的进一步发展值得期待：资金来源：惠康基金会、Bloomsbury Set 和 Cures Within Reach。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.