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

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.