- Title
- Application of pharmacometric methods in clinical toxinology
- Creator
- Sanhajariya, Suchaya
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Snakebite envenomation is an important medical problem causing significant morbidity and mortality in many countries worldwide, including Australia. Development of accurate risk assessment is crucial for the management of snake envenomation. The knowledge of the typical time course of venom exposure and clinical effects will be useful for developing accurate risk assessment, evaluating the effectiveness of intervention (e.g. antivenom therapy) on the clinical outcomes, and thus optimising the risk-benefit for individual patients. The overarching premise of this thesis was to apply pharmacometric principles to define the typical relationship between snake venom exposure and clinical effects over time in envenomed patients. A meta-analysis was conducted to bring together and explore the current knowledge surrounding snake venom, its compositions, clinical implications, and time course exposure (pharmacokinetics, PK) in both animals and humans. A preliminary population PK model of snake venom in snakebite patients was also developed from the data digitally extracted from the literature. PK of snake venom was commonly reported to exhibit a multi-compartment behaviour in animal studies. However, the population PK analysis of literature-derived snakebite data in patients found that snake venom exhibited a one-compartment behaviour with half-lives reported to be shorter than those found in animal studies. Snake venom PK in snakebite patients may exhibit a multi-compartment profile, but the data extracted were too sparse to support such behaviour. The influence of the different PK of snake toxins in the venom on the overall venom PK was subsequently examined using the stochastic simulation and estimation approach. The study revealed that venom data could not support more than a three-compartment model despite the venom being made of more than three toxins. The information on whole venom PK alone cannot provide a complete disposition profile of the individual toxin components in the venom. A population PK model was developed to describe the time course of Pseudechis porphyriacus (red-bellied black snake; RBBS) venom in patients receiving and not receiving antivenom therapy. P. porphyriacus venom was found to exhibit a one-compartment behaviour. The administration of antivenom was found to significantly increase the clearance of venom and reduce the concentrations to an undetectable level. The information on the exposure time of venom in the body following envenomation will help improve treatment and the timing of antivenom. Finally, myotoxicity following RBBS envenomation was investigated. An early administration of antivenom (within 6 hours post-bite) was found to reduce incidence of myotoxicity. A pharmacokinetic-pharmacodynamic (PKPD) model was developed to describe the relationship between the time course of venom (a mixture of toxins) and effect (elevation of creatine kinase concentration, a biomarker for myotoxicity). A kinetic-pharmacodynamic (KPD) model was also developed to describe the relationship between the time course of a theoretical toxin responsible for myotoxicity and effect. Based on the PKPD and KPD model developed, the information on venom or putative toxin concentration alone cannot predict the occurrence of myotoxicity in patients. The venom PK profile was found to be different from the putative toxin PK profile and hence did not appear to be an appropriate driver for the extent of myotoxicity. The work conducted in this thesis provide insights into the PK of snake venom and the implications for clinical management of venom effect. It is important to note that the venom PK alone does not provide a complete picture of the different toxin PK and we should not over-interpret PK studies when explaining the time course of biological effects in association with particular toxin fractions.
- Subject
- pharmacometrics; snake venom; envenomation; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1514153
- Identifier
- uon:56817
- Rights
- Copyright 2021 Suchaya Sanhajariya
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 14 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 343 KB | Adobe Acrobat PDF | View Details Download |