| Abstract | Snakebite is a neglected tropical disease and medical emergency that can result in rapid onset of local tissue-destruction and potentially lethal systemic haemorrhagic and/or neurotoxic pathologies. Snakebite primarily afflicts remote, impoverished, rural farming communities in regions with weak medical infrastructure. It annually kills approximately 138,000 people and 400,000 surviving victims suffer a substantially reduced quality of life due to the multiple effects of permanent physical and psychological disabilities. Antivenom is the only approved treatment at present, but this class of drug has many inherent limitations, including high-cost, poor safety, a requirement for intravenous delivery, and variable activity that tends to be limited to a small number of snake species. Most antivenoms have not been assessed in clinical trials and there is a great deal of uncertainty as to the optimal product, dose, dose frequency, and duration of treatment. LSTM is leading a multi-centre platform clinical trial in sub-Saharan Africa to help answer these questions. LSTM is also undertaking clinical trials of novel orally administered small molecule therapeutics that may offer an alternative to animal derived antivenoms. These drugs are safe, affordable, and can be taken orally soon after a bite and prior to arrival at hospital. We are leading a Phase II clinical trial to assess the efficacy of two products at sites in Africa and Brazil, but much uncertainly remains around the optimal dose, frequency of dosing and duration of treatment. In this project, we plan to leverage clinical samples collected from snakebite patients in LSTM-led clinical trials undertaken across sub-Saharan Africa and South America to better understand the pharmacokinetic-pharmacodynamic (PK-PD) relationship between snakebite therapies (oral drugs and antivenom), venom toxins and markers of envenoming. We will use snakebite coagulopathy as our primary model, and time course samples from envenomed patients collected over the duration of hospital stay, to investigate the relationship between the resolution of envenoming (i.e. restoration of normal blood clotting) with detectable plasma levels of drug/antivenom. We will also investigate the influencing role of venom concentrations and other relevant covariates that could influence the PK-PD relationship (e.g. body weight and renal function). The outcomes of this PhD studentship will inform appropriate dosing regimens of existing and new therapies for snakebite. The successful applicant will join the dynamic and well-funded team at LSTM’s Centre for Snakebite Research and Interventions (CSRI), providing stimulating interactions with laboratory scientists, clinicians and public health experts. |
| Where does this project lie in the translational pathway? | T1 - Basic Research,T2 - Human /Clinical Research |
| Expected outputs | Technical Outputs: - Define the association between drug levels and therapeutic effect - Develop data informed predictions relating to therapeutic dosing of snakebite therapies KE Impact: - Impactful policy informing research to improve dosing estimations of snakebite treatments - Data used to support regulatory approval submissions - REF-returnable publications Student Career Enhancement: - Acquisition of a variety of laboratory technical skills - Opportunities and mentorship to present biomedical research designed to address a neglected tropical disease at national and international conferences - Opportunities and mentorship to publish high-impact, influential papers - Potential opportunity to experience different academic environments with our collaborators - Numerous opportunities at LSTM to understand the diverse cultural, fiscal and medical barriers to good health in rural remote tropical regions |
| Training opportunities | The student will be exposed to a wide variety of research training opportunities, as they will join a well-funded, multi-disciplinary and dynamic team of clinicians, post docs, students and technicians. Thus, they will have an opportunity to acquire additional clinical and lab skill sets to those described above. In terms of career development, the student will receive ample and diverse training commensurate with developing an appropriately competitive CV for acquiring funding to support their career after the PhD. Funding will be available to support attendance of relevant external courses required for student skills development (e.g. in PK-PD modelling). |
| Skills required | A pharmacology background would be desirable. An interest in data analysis and modelling will be important. Critical thinking skills, a passion for research, and a meticulous nature, are highly sought after. |
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Key Publications associated with this project |
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4826081 |
| https://www.sciencedirect.com/science/article/pii/S0041010122001891 | |
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848174/ | |
| https://www.cell.com/trends/pharmacological-sciences/abstract/S0165-6147(21)00043-2 | |
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207661/ |