Bioequivalence prediction with small-scale biphasic dissolution and simultaneous dissolution-permeation apparatus-An...

Area of Science:

• Pharmacokinetics and Drug Development
• In Vitro-In Vivo Correlation Studies
• Biopharmaceutics

Background:

• Simple dissolution assays have limitations in predicting in vivo drug performance.
• Biphasic dissolution and dissolution-permeation (D-P) systems offer improved in vitro-in vivo correlation potential.
• Refinement of assay conditions and evaluation methods is crucial for effective use of these systems in drug development.

Purpose of the Study:

• To compare the predictive accuracy of small-volume D-P and biphasic dissolution systems for bioequivalence prediction.
• To investigate the impact of dose dependence on the predictive accuracy of these small-scale systems.
• To evaluate the use of whole in vitro flux profiles in mechanistic models for predicting drug absorption.

Main Methods:

• Comparison of a small-volume (16-20 mL) D-P system and a small-volume (40-80 mL) biphasic dissolution apparatus.
• Evaluation of five aripiprazole (ARP)-containing marketed drug products.
• Optimization of assay conditions, including dose reduction, to overcome system limitations.
• Application of mechanistic modeling (gastrointestinal unified theory) using whole in vitro flux profiles.

Main Results:

• Both systems achieved 100% accuracy in predicting bioequivalence for the maximum plasma concentration (Cmax) ratio with dose reduction strategies.
• Predictive accuracy for the area under the curve (AUC) ratio was dose-independent, with both apparatuses showing 100% accuracy.
• Mechanistic modeling using the entire in vitro flux profile accurately predicted fraction absorbed within the ±15% acceptance range.

Conclusions:

• Small-volume D-P and biphasic dissolution systems, when optimized, can accurately predict bioequivalence for Cmax and AUC ratios.
• Dose reduction is a key strategy to enhance the predictive performance of small-scale dissolution systems.
• The integration of comprehensive in vitro flux profiles into mechanistic models provides a robust approach for predicting drug absorption rates.