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
Currently, a large number of pharmaceutical companies focus on the development of (immunomodulatory) biotherapeutics such as recombinant proteins and monoclonal antibodies, developed for... Show moreCurrently, a large number of pharmaceutical companies focus on the development of (immunomodulatory) biotherapeutics such as recombinant proteins and monoclonal antibodies, developed for therapeutic and diagnostic purposes. The development of these biotherapeutics is challenging, among others due to a lack of robust efficacy data when administered to patients. Hence, the identification of selective, early phase biomarkers is particularly needed in their process of development. By the identification of these biomarkers (for instance using in vivo or ex vivo challenge models), question-based drug development together with the performance of concurrent engineering provides the opportunity to collect and connect data already in the early stages of drug development resulting in an earlier assessment of the potential value of a new (biotherapeutic) compound and a potential increase in the drug development success rates. This thesis provides an extended overview of different types of clinical pharmacology studies concerned with the complicated investigation of immunomodulatory biotherapeutics in the early stage of drug development. Key factors herein are the search for selective biomarkers in healthy volunteers and patients, the development of new methods, and optimization of existing methods to improve and potentially accelerate the development process of immunomodulatory biotherapeutics. Show less
