Doctoral Thesis
Application of integrative metabonomics in preclinical toxicology to augment drug development
Doctor of Philosophy (PhD), Murdoch University
2026
DOI:
https://doi.org/10.60867/00000190
Abstract
There is an urgent need to reduce the high drug attrition rates and number of serious adverse drug reactions (ADRs) caused by marketed pharmaceutical drugs. These issues underscore why it is a core goal of 21st century healthcare to provide more personalised medicine by improving the predictivity of models in the preclinical stages of the drug-development pipeline. Clinical chemistry biomarkers remain central to the detection and interpretation of systemic toxicity in preclinical studies, yet their robustness across toxicants, laboratories, and emerging technologies has not been comprehensively evaluated. In this PhD, I first compile a large-scale clinical chemical atlas of xenobiotic toxicity in the Sprague-Dawley rat, providing a reference resource for biomarker responses across multiple organ systems, which can be used as the raw input data to build predictive computational models for testing the potential toxicity of new candidate drugs. Building on this foundation, I use a suite of chemometric tools to investigate inter-laboratory clinical chemistry parameter variation in seven-day acute hydrazine toxicity studies in the Sprague-Dawley rat. This pipeline demonstrated both the reproducibility and site-specific variability of commonly used clinical parameters. Finally, I explore the potential of NMR-based metabolic profiling as a complementary approach to conventional clinical chemistry, assessing agreement and divergence between platforms, and identify molecular signatures of hepatic enzymes and other clinical chemistry parameters. Further, I identify new metabolic correlates of clinical chemical data while critically evaluating their limitations and highlight opportunities for methodological innovation. Together, these studies provide valuable input data for predictive modelling, strengthen confidence in existing biomarkers, and identify new molecular signatures of toxicity. This thesis was conducted in alignment with the 3Rs (Replace, Reduce, Refine) to repurpose existing data and enhance the reliability of toxicity biomarkers and advance the modernisation of biomarker strategies in preclinical toxicology. This will contribute to reducing the number of serious ADRs and work towards the goal of personalised healthcare.
Details
- Title
- Application of integrative metabonomics in preclinical toxicology to augment drug development
- Authors/Creators
- Janonna Kadyrov
- Contributors
- Elaine Holmes (Supervisor) - Murdoch University, Centre for Computational and Systems MedicineJulien Wist (Supervisor) - Murdoch University, Centre for Computational and Systems MedicineJeremy Nicholson (Supervisor) - Murdoch University
- Awarding Institution
- Murdoch University; Doctor of Philosophy (PhD)
- Identifiers
- 991005932916807891
- Murdoch Affiliation
- School of Medical, Molecular and Forensic Sciences; Centre for Computational and Systems Medicine
- Resource Type
- Doctoral Thesis
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