Intestinal PBPK Modelling for Gut-Targeted Drugs
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.,
How can intestinal PBPK modelling improve predictions of local drug exposure for gut-targeted therapies?
Drug developers can use intestinal PBPK modelling to mechanistically predict gastrointestinal target site concentrations and gain insight into local exposure that cannot be inferred from plasma data alone. By informing models with systemic plasma, portal vein, mucus and regional intestinal tissue concentrations, intestinal PBPK models can help more fully characterize intestinal absorption and distribution of gut-targeted therapies to aid translation confidence, predict doses, and support exposure-activity relationships.
Download the poster by filling out the form to the right.
Key Takeaways for Gut-Targeted Drug Development:
Measure exposure closer to the intestinal target
Oral drugs designed for restricted gastrointestinal distribution aim to achieve local activity while minimising systemic exposure. For these therapies, plasma concentrations may provide limited mechanistic insight into the concentrations driving activity within the gastrointestinal tract.
Portal vein concentrations/exposure as well as exposure in intestinal lumen/mucus/mucosa and other tissue layers may provide translational PKPD modelling with more pertinent information. Regional gastrointestinal tissue concentrations are difficult to measure directly.
Capabilities
Combine multiple biological matrices
A mechanistic, multi-endpoint rat study was developed using izenticitinib, also known as TD-1473, as a model gut-restricted JAK inhibitor. The study characterised:
- Systemic plasma exposure
- Portal vein exposure
- Regional gastrointestinal tissue concentrations
- Intestinal mucus concentrations
- Exposure across the duodenum, jejunum, ileum and colon
Combining these matrices provided a more detailed understanding of intestinal absorption and local distribution than systemic plasma measurements alone.
Build an in vivo-informed intestinal PBPK model
The resultant rat PBPK model was built on the GastroPlus GPX.2 ACAT+ platform. Compound-specific physicochemical properties were used along with in vitro/in vivo ADME/pharmacokinetic data to model oral absorption, regional gastrointestinal distribution, and systemic exposure.
The ACAT+ framework was used to represent drug transit and absorption along the gastrointestinal tract, while regional modelling enabled the assessment of concentrations within intestinal tissue layers.
Improve predictions of local intestinal exposure
The model described the observed systemic and portal vein plasma concentration-time profiles and captured regional gastrointestinal tissue concentrations measured in vivo. Including both systemic and portal vein compartments improved prediction of gastrointestinal tissue exposure.
Portal vein concentrations provided a closer representation of the gastrointestinal biophase than systemic plasma because drug absorbed from the gastrointestinal tract enters the portal circulation before passing through the liver. Predicted gastrointestinal tissue concentrations were also consistent with observed colonic tissue exposure.
Support translation to human studies
By integrating systemic, portal vein, tissue and mucus data, this approach improves the mechanistic understanding of intestinal absorption and distribution. It also increases confidence in the development of human PBPK models and human dose predictions for gut-targeted therapies.
The next stage of this work focuses on human translational studies, including modelling clinical plasma and gastrointestinal tissue exposure, with the aim of linking local intestinal concentrations to target engagement and clinical efficacy.
Final takeaway: For locally acting gastrointestinal drugs, combining targeted in vivo measurements with mechanistic intestinal PBPK modelling can provide a stronger basis for assessing local exposure, supporting human translation and informing dose selection.
What is in the poster
This poster shows how multi-matrix exposure data and intestinal PBPK modelling can be combined to better predict local gastrointestinal drug exposure and support the development of gut-targeted therapies. Complete the form to download it.
Frequently asked questions
Why aren’t plasma concentrations enough for gut-targeted drugs?
Systemic plasma concentrations may not reflect drug levels at the site of action within the gastrointestinal tract. Measuring portal vein, mucus and intestinal tissue exposure can provide a more complete understanding of local drug distribution.
What is intestinal PBPK modelling used for?
Intestinal PBPK modelling is used to predict drug absorption, distribution and tissue exposure throughout the gastrointestinal tract. It can help support dose selection and human translation for gut-targeted therapies.
How can intestinal PBPK models improve confidence in human studies?
By combining experimental exposure data with mechanistic modelling, intestinal PBPK models can better predict local tissue concentrations and support translation from preclinical studies to humans.
Explore Pharmaron’s intestinal PBPK modeling approach.
References
1.DeSesso et al., Food and Chemical Toxicology 2000; 39:209-228