Digitalizing the TIM-1 Model using Computational Approaches-Part One: TIM-1 Data Explorer

Area of Science:

• Pharmacokinetics and Drug Metabolism
• In Vitro Drug Testing Technologies

Background:

• The TIM-1 gastrointestinal model simulates the human digestive system for biorelevant dissolution testing.
• Current use of TIM-1 data is primarily qualitative, limiting quantitative pharmacokinetic predictions.
• Physiologically based pharmacokinetic (PBPK) modeling requires more detailed input than standard bioaccessibility data.

Purpose of the Study:

• To develop a computational tool, TIM-1 Data Explorer, for detailed analysis of fluid and mass balance in the TIM-1 system.
• To expand the utility of TIM-1 model data beyond bioaccessibility for quantitative predictions.
• To enable in-depth interpretation of TIM-1 experimental data, including drug dissolution and precipitation.

Main Methods:

• Development of the TIM-1 Data Explorer computational tool.
• Validation of the tool using two case studies involving paracetamol and a weakly basic compound (PF-07059013).
• Analysis of mass balance, dissolution, and precipitation processes within the TIM-1 system.

Main Results:

• The TIM-1 Data Explorer successfully describes fluid and mass balance within the TIM-1 system.
• The tool accurately models mass transfer events, as demonstrated with paracetamol.
• Dissolution and precipitation processes were effectively described for a weakly basic compound using the TIM-1 Data Explorer.

Conclusions:

• The TIM-1 Data Explorer significantly enhances the quantitative application of TIM-1 gastrointestinal model data.
• This tool facilitates more accurate PBPK modeling and supports improved drug product design.
• The computational tool provides deeper insights into drug behavior within the simulated gastrointestinal environment.