TRUE-1: Trial of Repurposed Unithiol for snakebite Envenoming phase 1 (safety, tolerability, pharmacokinetics and pharmacodynamics in healthy Kenyan adults)

Wellcome Open Research

article

Michael Abouyannis¹  Richard FitzGerald³  Mwanajuma Ngama²  Hope Mwangudzah²  Yvonne K. Nyambura²  Samson Ngome²  Debra Riako²  Lawrence Babu²  Frida Lewa²  Laura Else⁴  Sujan Dily Penchala⁴  Benedict Orindi²  Noni Mumba²  Betty Kalama²  Francis M. Ndungu²  Ifedayo Adetifa²  Saye Khoo³  David G. Lalloo¹  Nicholas R. Casewell¹  Mainga Hamaluba² 

[1] Centre for Snakebite Research & Interventions, Liverpool School of Tropical Medicine;KEMRI-Wellcome Research Programme;NIHR Royal Liverpool and Broadgreen CRF, Liverpool University Hospitals NHS Foundation Trust;Department of Molecular and Clinical Pharmacology, University of Liverpool;Department of Infectious Diseases Epidemiology, London School of Hygiene & Tropical Medicine;Centre for Drugs & Diagnostics, Liverpool School of Tropical Medicine;Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford

关键词: Snakebite;    envenoming;    small molecule;    chelator;    phase I;    adaptive;    repurpose;    clinical trial.;   

DOI  :  10.12688/wellcomeopenres.17682.1

学科分类：内科医学

来源: Wellcome

【 摘 要 】

Background: Snakebites affect over 5 million people each year, and over 100,000 per year die as a result. The only available treatment is antivenom, which has many shortcomings including high cost, intravenous administration, and high risk of adverse events. One of the most abundant and harmful components of viper venoms are the zinc-dependent snake venom metalloproteinases (SVMPs). Unithiol is a chelating agent which is routinely used to treat heavy metal poisoning.In vivo experiments in small animal models have demonstrated that unithiol can prevent local tissue damage and death caused by a certain viper species. This phase I clinical trial will assess the safety of ascending doses of unithiol with a view for repurposing for snakebite indication.Methods: This open label, single agent, phase I clinical trial of a repurposed drug has a primary objective to evaluate the safety of escalating doses of unithiol, and a secondary objective to describe its pharmacokinetics. In total, 64 healthy Kenyan volunteers from Kilifi County will be dosed in consecutive groups of eight, with dose escalation decisions dependent on review of safety data by an independent data safety monitoring board. Four groups will receive ascending single oral doses, two will receive multiple oral doses, and two will receive single intravenous doses. Follow-up will be for 6-months and includes full adverse event reporting. Pharmacokinetic analysis will define the Cmax, Tmax, half-life and renal elimination.Conclusions: This clinical trial will assess the safety and tolerability of a promising oral therapeutic in a relevant setting where snakebites are prevalent. Unithiol is likely to be safer than antivenom, is easier to manufacture, has activity against diverse snake species, and can be administered orally, and thus shows promise for repurposing for tropical snakebite.

【 授权许可】

CC BY