Digitalizing the TIM-1 Model Using Computational Approaches─Part Two: Digital TIM-1 Model in GastroPlus.

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Computational Modeling and Simulation
• Drug Product Development

Background:

• The TIM-1 model simulates gastrointestinal conditions to predict in vivo drug release and bioavailability.
• Accurate prediction of bioaccessible drug fractions is crucial for nonclinical drug development.
• Existing models require validation for diverse physiological and formulation conditions.

Purpose of the Study:

• To develop and validate a digital TIM-1 model within the GastroPlus platform.
• To assess the model's ability to predict luminal concentrations and bioaccessible fractions.
• To evaluate the digital TIM-1 model's performance in predicting drug behavior under different physiological conditions.

Main Methods:

• Development of a digital TIM-1 model integrated into the GastroPlus software.
• Validation experiments using two marker compounds under fed and fasted states.
• Case study with PF-07059013 at varying doses and achlorhydric conditions.

Main Results:

• The digital TIM-1 model accurately reflected luminal concentrations and bioaccessible fractions for marker compounds.
• Model predictions aligned with experimental data for PF-07059013, particularly showing achlorhydric effects on solubility-limited dissolution.
• The model demonstrated appropriate integration of mass transfer and predicted dose-dependent effects.

Conclusions:

• The validated digital TIM-1 model in GastroPlus is a reliable tool for predicting in vitro drug release and bioavailability.
• This digital model facilitates the assessment of critical bioavailability attributes and aids in formulation development.
• Future applications include establishing in vitro-in vivo correlations (IVIVC) for enhanced drug development.