Inter- and Intraspecies extrapolation for the exploration of the pharmacokinetics in untapped populations

Abstract

The inclusion and exclusion criteria used in clinical trials pose an obstacle to the external validity of anticancer treatments in certain populations, requiring a different approach to obtain this information. Prior to administering a drug to humans or a new population, such as children, it is necessary to predict the exposure, efficacy, and toxicity as accurate as possible, especially for highly toxic drugs such as anticancer drugs. Model-based and physiologically informed extrapolation can help to obtain valuable information and increase safety in drug development for these populations. The focus of this thesis was on interspecies scaling of pharmacokinetics (PK) in mice to humans and intraspecies scaling of amounts of cytotoxic agents in maternal breast milk to exposure in infant and its subsequent safety. With modeling approaches, the aim was to optimally exploit available preclinical data and evaluate the predictability of the human exposure with genetically modified mouse models. Furthermore, the distribution of different cytotoxic agents to breast milk was assessed to inform the predictions of exposure in infants should they ingest this breast milk containing cytotoxic agents.