Promotor: Prof.dr. M. Danhof
|Links||Thesis in Leiden Repository|
This thesis focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is proposed to 1) ensure that pharmacological concepts are incorporated into the evaluation of safety and toxicity; 2) facilitate the integration of historical evidence and thereby the translation of findings across species; and 3) promote the use of experimental protocols tailored to address specific safety and toxicity questions. Nonlinear-mixed effects modelling is recommended as a tool to account for such requirements. Our goal was to explore the feasibility of a model-based approach to toxicology assessment and risk prediction in humans and, where possible, to compare the performance of this approach to traditional safety assessment approaches. The investigational plan of the thesis was divided into two sections where the development of methodology is followed by a case study with real data. A variety of analysis strategies and protocol designs are investigated where we set the constraint that proposals to deviate from existing protocols be minimal. We finally compile recommendations for protocol optimisation and data analysis/interpretation strategies to facilitate the implementation of model-based techniques in safety pharmacology and toxicology research.