Using pH Gradient Dissolution with In-Situ Flux Measurement to Evaluate Bioavailability and DDI for Formulated Poorly...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Pharmaceutical Technology
• Drug Interactions

Background:

• Acid reducing agents (ARAs) can significantly alter gastrointestinal pH, impacting the bioavailability of certain drugs.
• Drug-drug interactions (DDIs) involving ARAs are a concern, necessitating predictive in vitro tools.
• Assessing the risk of bioavailability reduction due to DDIs from ARAs is crucial for drug development.

Purpose of the Study:

• To develop and validate an in vitro pH-gradient dissolution method combined with flux measurements.
• To assess the risk of bioavailability reduction caused by DDIs involving ARAs.
• To correlate in vitro findings with in vivo pharmacokinetic data.

Main Methods:

• A pH-gradient dissolution method was employed using USP II dissolution vessels with integrated absorption chambers.
• Fiber optic UV-probes were used for in situ concentration monitoring.
• Dissolution testing was performed on BCS Class II drugs (GDC-0810, GDC-0941, compound A) with media pH conversion from 1.6 or 4.0 to FaSSIF.

Main Results:

• GDC-0810 showed no significant flux difference between pH conditions.
• GDC-0941 exhibited a 95% flux decrease in the pH 4.0 to FaSSIF experiment due to low solubility, correlating with in vivo Cmax and AUC reductions.
• Compound A demonstrated a 25% flux reduction with pH change, aligning with clinical AUC data.

Conclusions:

• The developed in vitro pH-gradient dissolution method accurately predicts bioavailability changes caused by ARAs.
• The method provides a valuable tool for formulators to mitigate DDIs from ARAs during drug product development.
• Good correlation between in vitro and in vivo data validates the method's applicability.