Integrating Dynamic in vitro Systems and Mechanistic Absorption Modeling: Case Study of Pralsetinib

Area of Science:

• Pharmacokinetics and Drug Metabolism
• In Vitro and In Silico Modeling
• Gastrointestinal Physiology

Background:

• Predicting human oral drug absorption is crucial for drug development.
• Dynamic in vitro systems and physiologically based pharmacokinetic (PBPK) modeling are promising but often used separately.
• Pralsetinib, a RET inhibitor, exhibits BCS Class II properties (low solubility, high permeability), posing absorption challenges.

Purpose of the Study:

• To integrate dynamic in vitro absorption systems with PBPK modeling.
• To investigate the oral absorption of pralsetinib using a combined approach.
• To enhance the prediction of human oral absorption for low-solubility compounds.

Main Methods:

• Utilized the Tiny-TIM dynamic in vitro model simulating human gastrointestinal conditions.
• Conducted Tiny-TIM experiments with pralsetinib at 200 mg and 400 mg under fasting conditions.
• Employed Simcyp PBPK software (V21) for mechanistic absorption modeling, incorporating Tiny-TIM solubility data.

Main Results:

• Pralsetinib fasted bioaccessibility was 63% (200 mg) and 53% (400 mg) in Tiny-TIM.
• A 16% reduction in bioaccessibility was noted at 400 mg under elevated gastric pH.
• PBPK modeling predicted similar absorption fractions across doses, aligning with observed exposure.

Conclusions:

• Integrating dynamic in vitro systems with PBPK modeling offers a robust approach for predicting human oral absorption.
• This integrated strategy is particularly valuable for challenging low-solubility compounds like pralsetinib.
• The study demonstrates the utility of combining experimental and computational methods for pharmacokinetic predictions.