Development of a repurposed orally available small molecule snakebite therapeutic: clinical need, safety, pharmacokinetics, and proposed methods to assess efficacy

Abouyannis, Michael ORCID: https://orcid.org/0000-0003-4856-4334 (2024) Development of a repurposed orally available small molecule snakebite therapeutic: clinical need, safety, pharmacokinetics, and proposed methods to assess efficacy, Thesis (Doctoral), Liverpool School of Tropical Medicine.

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Abstract

Introduction
Snakebite is a priority neglected tropical disease that predominantly affects children and young adults in Asia and Africa. There is a large burden of local tissue damage amongst children in Africa.
Zinc dependent snake venom metalloproteinase enzymes cause systemic haemorrhage, venom-induced consumption coagulopathy, and local tissue damage, and can be inhibited by unithiol although the current low dose oral regimen could be optimised. As the pipeline of snakebite therapeutics expands, and with a shift toward products that aim to inhibit toxin classes across a wide geographic range of snake species, there is an urgent need to agree on globally standardised clinical trial outcome measures.

Aims
1. Describe the burden of paediatric snakebite in Kilifi County, Kenya.
2. Evaluate the safety of increased oral doses of unithiol amongst healthy volunteers in Kilifi.
3. Undertake an interim pharmacokinetic analysis to inform a short-course high-dose multiple dosing regimen of unithiol.
4. Develop a core outcome measurement set to support future clinical trials of snakebite therapeutics.
Cases of paediatric snakebite presenting to Kilifi County Hospital between 2003 and 2021 were prospectively registered. The population incidence and mortality rate were calculated, and independent predictors of severe local tissue damage were identified.
A phase I clinical trial of unithiol was undertaken. The single ascending dose stage escalated from a standard oral dose of 300 mg up to 1,500 mg. The interim pharmacokinetic analysis informed a short-course multiple dosing regimen, which was evaluated for safety. Established intravenous doses of 3 and 5 mg/kg were administered to gather pharmacokinetic data for these regimens. A comprehensive list of snakebite clinical trial outcome measures was identified by a systematic review. Through a process of shortlisting by questionnaire and a series of consensus meetings with voting, a globally representative group of stakeholders agreed on a core outcome measurement set.

Results
The population incidence of hospital-attended snakebite in Kilifi County, Kenya, was 11.3 and 29.1 per 100,000 person-years for children aged ≤5-years and 6-12 years, respectively. There were five snakebite associated deaths during the study period. Low haemoglobin, raised white cell count, and an upper limb bite site were associated with severe local tissue damage. Oral unithiol was safe and well tolerated throughout the single and multiple dose escalations. The 1,500 mg oral dose demonstrated a Cmax of 15.6 µg/mL, Tmax of 3 hours, T1/2 of 18.4 hours and AUC0- last of 180.9 (h.µg/mL). There was a likely causal relationship between dosing and raised alanine transferase, although this spontaneously resolved with no complications in all cases.
A globally relevant core outcome measurement set was developed, which provides standardised measures of mortality, disability, and allergic reactions. Syndrome specific outcome measures were developed to allow the tool to be adaptable depending on the biting species.

Conclusions
The incidence of snakebite envenoming in Kilifi was high amongst children, and the main pathology was of local envenoming. Unithiol is a safe, affordable, and orally available repurposed therapeutic that shows promise as a broad spectrum SVMP inhibitor. As unithiol and other therapeutics progress to clinical trials, the core outcome measurement set is anticipated to improve the quality of trial designs and support future meta-analyses

Item Type:	Thesis (Doctoral)
Subjects:	QV Pharmacology > QV 38 Drug action. QV Pharmacology > Toxicology > General Toxicology > QV 601 Antidotes and other therapeutic measures WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles
Repository link:	Item title Item URI A long-term observational study of paediatric snakebite in Kilifi County, south-east Kenya https://archive.lstmed.ac.uk/22849/ TRUE-1: Trial of Repurposed Unithiol for snakebite Envenoming phase 1 (safety, tolerability, pharmacokinetics and pharmacodynamics in healthy Kenyan adults) https://archive.lstmed.ac.uk/20165/ Clinical outcomes and outcome measurement tools reported in randomised controlled trials of treatment for snakebite envenoming: A systematic review https://archive.lstmed.ac.uk/18759/ A global core outcome measurement set for snakebite clinical trials. https://archive.lstmed.ac.uk/21833/
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Depositing User:	Lynn Roberts-Maloney
Date Deposited:	22 Apr 2024 11:17
Last Modified:	22 Apr 2024 11:22
URI:	https://archive.lstmed.ac.uk/id/eprint/24435

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