Effect of pH on colloidal structures in human intestinal fluids and intestinal absorption of anticancer drugs

Oral administration followed by intestinal absorption is the preferred way to deliver drugs to the body. Therefore, estimating the

correct oral dose to achieve a therapeutic effect is an important challenge when developing drug products. Predicting intestinal drug

absorption needs to consider multiple influencing factors, including properties of the drug, the formulation, and the human intestinal

fluids (HIF). One of the critical factors of HIF is pH, as it may influence intestinal drug absorption both directly and indirectly. The direct

effect of pH on a drugs ionisation state and, subsequently, intestinal absorption is widely known. However, the effect of pH on the

solubilisation and absorption of lipophilic drugs by changing the colloidal structures present in HIF, has not yet been systematically

analysed.

Understanding this indirect pH effect is especially needed to improve dose predictions for drugs with a narrow therapeutic window

such as anticancer drugs, and address both inefficiency and potential side effects. The proposed project therefore aims to understand

and predict the pH effect on colloidal structures in HIF and how it affects the absorption potential of anticancer drugs in both fasted

and fed state conditions.

To achieve its goal, the project combines the expertise of the host group at KU Leuven in absorption profiling using in vitro and in

vivo methods with the applicants experience in predictive in silico modelling. This approach will provide unique insights into the

indirect pH effect on drug absorption and contribute to the development of in silico predictive models to guide the early-stage

formulation and dose optimisation of anticancer drugs. As such, the project will have important value for pipelining new anticancer

drugs and will benefit the European Commission priorities for 2019-2024, such as the pharmaceutical strategy and Europes Beating

Cancer Plan.