In this thesis, mathematical modeling and simulation was applied as a tool to inform quantitative decision making in oncology drug discovery and development. Modeling based approaches were shown to... Show moreIn this thesis, mathematical modeling and simulation was applied as a tool to inform quantitative decision making in oncology drug discovery and development. Modeling based approaches were shown to be useful to understand the mechanism of action and deconvolve the complexities of novel biotherapeutic modalities being used to treat cancer, including monospecific and bispecific monoclonal antibodies and antibody drug conjugates. Several key observations and learnings were made. For example, modeling was shown to be a useful method to reduce animal experimentation, by enabling in vitro to in vivo correlations or use of simulation to replace experimental methodologies. Mechanism based modeling and simulation was found to be a useful means to translate from preclinical studies to the clinic to ensure progression of the best drug to clinical trials. These models could then be used to optimize design of clinical studies from selection of starting doses to recommended efficacious doses for pivotal trials. Modeling was shown to be beneficial to understand variability in the clinic and to identify factors impacting drug response in individual patients, paving the way for precision medicine strategies, informing clinical diagnostics, biomarkers, and doses for different oncology indications. Show less
The zebrafish is a promising vertebrate model organism in early drug discovery and development. Translation of pharmacological findings to higher vertebrates requires quantification of the... Show moreThe zebrafish is a promising vertebrate model organism in early drug discovery and development. Translation of pharmacological findings to higher vertebrates requires quantification of the underlying pharmacological and (patho)physiological processes. In this thesis, we therefore developed and integrated innovative experimental and computational methods for the successful quantification of 1) the internal exposure over time after waterborne drug treatment, 2) disease dynamics and drug-induced changes therein, and 3) between-species differences in disease mechanisms. The state-of-the-art methods that we developed included nanoscale blood sampling, sensitive LC-MS/MS methods for drugs and their isomers and metabolites, and three-dimensional microscopy, integrated with non-linear mixed effects modelling to quantify the pharmacological processes in this small vertebrate. This multidisciplinarity enabled quantification of internal drug exposure-response relationships, contributed to positioning the zebrafish in the preclinical drug development pipeline, and inspired continuous collaborations between experimental and computational scientists. Show less
The main objective of the research described in this thesis is to demonstrate the relevance of biomarkers on the selection of the dose range of COX inhibitors for effective analgesic and anti... Show moreThe main objective of the research described in this thesis is to demonstrate the relevance of biomarkers on the selection of the dose range of COX inhibitors for effective analgesic and anti-inflammatory response, as opposed to the focus on behavioural measures of pain and inflammation advocated by the current paradigm for the development of non-steroidal anti-inflammatory drugs (NSAIDs). To this end, the relationship between drug concentration and the corresponding inhibition of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) was investigated for a range of COX inhibitors with varying degrees of selectivity, and hence with differential effects on the selected biomarkers. Thanks to the use of a mechanism-based approach, attention is also given to translational pharmacology in drug development. We evaluate whether 1) estimates of drug action in vitro are predictive of the effect in vivo, 2) animal data in vivo reflect drug effect on biomarkers in humans and 3) whether inflammatory conditions modify the extent of drug effect as compared to healthy conditions. A recommendation and guideline for best practices in the development of COX inhibitors is anticipated from this analysis. Show less
