From lab-to-clinic with model informed formulation development: a case study of hydroxyzine SR tablets

Area of Science:

• Pharmacokinetics and Drug Delivery
• Computational Modeling in Pharmaceutical Science

Background:

• Model Informed Formulation Development (MIFD) integrates physiologically based pharmacokinetic (PBPK) modeling and in silico tools for efficient new product development.
• Hydroxyzine, an antihistamine, has a significant side effect of sedation, necessitating optimized drug delivery to manage its therapeutic profile.

Purpose of the Study:

• To develop a sustained-release formulation for Hydroxyzine using MIFD to reduce peak plasma concentrations and minimize sedation.
• To validate the developed formulation's performance through in vivo bioequivalence studies and in silico predictions.
• To establish clinically relevant dissolution specifications and assess the food effect for the modified-release Hydroxyzine product.

Main Methods:

• Development of a preliminary PBPK absorption model using immediate-release Hydroxyzine data.
• In silico evaluation of various hypothetical dissolution profiles to guide formulation design.
• Manufacturing of a sustained-release formulation using Matrixeal™ technology.
• Conducting preliminary and confirmatory bioequivalence (BE) studies in human volunteers.
• Refinement of the PBPK model based on bioequivalence study results.

Main Results:

• A sustained-release Hydroxyzine formulation was successfully developed, demonstrating reduced peak plasma concentrations.
• Virtual BE studies accurately predicted the performance of the modified formulation.
• Confirmatory BE studies in 70 volunteers under fasting conditions validated the new formulation.
• Clinically relevant dissolution specifications were established, and the food effect was assessed.

Conclusions:

• PBPK modeling is a valuable tool for the development of modified-release drug products, as demonstrated by the Hydroxyzine sustained-release formulation.
• MIFD enables efficient product development by predicting in vivo performance and guiding formulation optimization.
• The developed Hydroxyzine formulation offers a potentially improved therapeutic profile with reduced sedation.