Biopharmaceutic Assessment of Post-Approval Changes for Azithromycin Immediate Release Tablets Using Predictive In...

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery and Formulation
• Pharmacokinetics and Pharmacodynamics

Background:

• Post-approval changes (PACs) in drug formulations necessitate risk assessment for safety and efficacy.
• Azithromycin, with a controversial biopharmaceutics classification system (BCS) classification, often requires standard bioequivalence trials.
• Predictive in vitro dissolution and modeling offer surrogate techniques for biopharmaceutical assessment.

Purpose of the Study:

• To assess the risks associated with post-approval changes in azithromycin immediate-release (IR) tablets.
• To evaluate a model-informed approach integrating predictive dissolution for formulation assessment.
• To determine if bioequivalence studies can be waived for azithromycin formulations with PACs.

Main Methods:

• Compared two bioequivalent batches and a new test formulation using in vitro dissolution in gastric and surrogate media.
• Utilized reversible non-equilibrium and Mooney's models to characterize surrogate media for azithromycin IR.
• Created a virtual population using dissolution data and pharmacokinetic information to simulate virtual bioequivalence via a series resistance model.

Main Results:

• The new azithromycin formulation exhibited faster dissolution in gastric media but comparable dissolution in surrogate media.
• A series resistance model indicated that drug absorption is primarily rate-limited by permeability, not dissolution.
• Virtual bioequivalence simulations corroborated the findings that permeability is the rate-limiting step.

Conclusions:

• The study demonstrated the potential of integrating predictive dissolution into a model-informed PACs (MIPACs) approach.
• A waiver for bioequivalence studies for azithromycin may not be justified without further evaluation of excipient effects on permeability.
• Model-informed approaches can aid in the risk assessment of PACs for complex formulations.