Intestinal PBPK Modelling for Gut-Targeted Drug Development
Poster Authors:
Simon TaylorA, Dave LugoA, Simon TeagueA, Elnaz GozalpourA, Honglei WangB, Hongwen DuB, Hongyu ZhouB
A Pharmaron, Hoddesdon, UK
B Pharmaron Beijing, Co. Ltd.,
Download Poster: Optimising Intestinal Tissue Exposure of Locally Acting Drugs Using an In Vivo-Informed PBPK Modelling Approach
In order to develop a gut-targeted therapy, researchers require a clear understanding of drug exposure within the gastrointestinal tract, not just systemic circulation. For locally acting drugs, exposure in the intestinal lumen, mucus, and tissue layers can be more relevant to efficacy than plasma concentrations alone. In this poster we show how a mechanistic in vivo-informed intestinal PBPK modelling approach can improve understanding of regional intestinal exposure and support translation from preclinical studies to humans.
Key Takeaways:
A mechanistic rat study with multiple end points was used to characterise systemic plasma, portal vein, intestinal tissue and mucus exposure for the gut-restricted JAK inhibitor izenticitinib. The data from this study supported the further development of a gastrointestinal-focused PBPK model capable of describing both systemic and local intestinal exposure. The model accurately captured observed plasma and intestinal tissue concentrations and provides a framework for improving human translation and dose prediction for gut-targeted therapies.
Capabilities
Gut-targeted therapies pose distinct challenges. Oral drugs designed for restricted gastrointestinal distribution are increasingly being developed to maximise local activity while minimising systemic exposure. However, conventional pharmacokinetic assessments typically focus on plasma concentrations, which may provide limited insight into the drug concentrations that drive activity at intestinal targets. Direct measurement of regional gut tissue exposure is technically challenging, creating a need for predictive modelling approaches that can bridge this gap.
To better understand intestinal drug distribution, Pharmaron developed a mechanistic study design incorporating:
- Systemic plasma exposure
- Portal vein exposure
- Regional GI tissue concentrations
- Intestinal mucus concentrations
These data were used to build a PBPK model in GastroPlus® using the ACAT+ framework, enabling mechanistic representation of regional absorption and GI distribution processes
The Results:
The PBPK model successfully described systemic and portal vein pharmacokinetic profiles while capturing regional gastrointestinal tissue concentrations observed in vivo. Inclusion of portal vein data improved model performance and provided a more relevant assessment of drug exposure at intestinal target sites. Predicted gastrointestinal tissue concentrations aligned with observed colonic exposure, increasing confidence in the model’s ability to support human translation.
The work also highlighted the value of combining multiple biological matrices to improve mechanistic understanding of intestinal absorption and drug distribution. This richer dataset enabled the development of a more physiologically relevant PBPK model than would be possible using plasma data alone.
This approach has a number of applications in drug discovery and development. It provides a framework for understanding local gastrointestinal exposure and supporting the development of gut-targeted therapies. By integrating in vivo exposure data with mechanistic PBPK modelling, we show how researchers can improve confidence in human translation, optimise candidate selection, and support dose prediction for compounds where tissue exposure is a key determinant of efficacy. The strategy may also help link local drug concentrations with target engagement and clinical outcomes, supporting more informed decision-making throughout development
Why Pharmaron?
Pharmaron combines advanced DMPK expertise with PBPK modelling capabilities to support the development of locally acting and systemically active therapies. Our integrated approach spans in vitro ADME, preclinical pharmacokinetics, translational modelling, bioanalysis and PBPK simulation, helping clients make better-informed decisions from discovery through clinical development.
