In Vivo Predictive Dissolution and Biopharmaceutic-Based In Silico Model to Explain Bioequivalence Results of...

Area of Science:

• Pharmacokinetics and Biopharmaceutics
• Drug Formulation and Delivery
• In Vitro-In Vivo Correlation (IVIVC)

Background:

• Bioequivalence (BE) prediction for fixed-dose combination products is challenging due to differing drug properties (e.g., BCS Class IV valsartan and BCS Class III hydrochlorothiazide).
• Excipient-dependent gastrointestinal variables significantly impact drug exposure, necessitating advanced modeling approaches.

Purpose of the Study:

• To predict the in vivo bioequivalence (BE) outcome of valsartan (VALS) and hydrochlorothiazide (HCTZ) from fixed-dose combination products.
• To establish an in vitro-in vivo relationship (IVIVR) using a gastrointestinal simulator (GIS) and a physiologically based biopharmaceutic model (PBBM).

Main Methods:

• Dissolution testing of three oral fixed-dose combination products (one reference, two generic) in a GIS.
• Construction of a PBBM for valsartan, incorporating excipient-affected gastrointestinal variables (permeability, GI transit time) into the IVIVC model.
• Characterization of valsartan permeability using in situ perfusion in rats and estimation of GI transit times from HCTZ in vivo data.

Main Results:

• The PBBM successfully fitted the in vivo BE results with a low prediction error.
• The model demonstrated the ability to predict BE outcomes for valsartan, a BCS Class IV compound.
• The study confirmed the significant impact of formulation excipients on drug exposure via altered GI variables.

Conclusions:

• Physiologically based biopharmaceutic modeling (PBBM) is a valuable tool for predicting bioequivalence of complex drug formulations.
• Incorporating gastrointestinal critical variables beyond dissolution is crucial for accurate IVIVC, especially for BCS Class IV drugs.
• This approach enhances the understanding of drug absorption and formulation impact, aiding in generic drug development.