Biorelevant Two-Stage In Vitro Testing for rDCS Classification and in PBPK Modeling-Case Example Ritonavir

Area of Science:

• Pharmaceutical Sciences
• Drug Development
• In Vitro Testing

Background:

• Biorelevant two-stage in vitro testing is crucial for drug development applications.
• Key uses include drug classification, predicting gastrointestinal concentrations, and pharmacokinetic modeling.

Purpose of the Study:

• To assess the supersaturation and precipitation behavior of ritonavir using two-stage in vitro testing.
• To compare two-stage testing results with a complex "transfer" model for Norvir® formulations.
• To integrate in vitro data into physiologically based pharmacokinetic models.

Main Methods:

• Utilized a two-stage in vitro testing approach for ritonavir.
• Employed a "transfer" model for comparative analysis.
• Applied the in vitro data Analysis Toolkit for mechanistic modeling.
• Integrated data into the Simcyp Simulator for physiologically based pharmacokinetic modeling.

Main Results:

• Two-stage testing provided results comparable to the "transfer" model for ritonavir formulations.
• Demonstrated the supersaturation and precipitation behavior of amorphous solid dispersions.
• Successfully integrated solubility and two-stage data into a pharmacokinetic model.

Conclusions:

• Two-stage in vitro testing is a reliable method for evaluating drug behavior, particularly for amorphous solid dispersions like ritonavir.
• This approach supports the refined Developability Classification System and enhances physiologically based pharmacokinetic modeling.
• The findings facilitate more accurate predictions of drug performance in vivo.