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Physiologically Based Pharmacokinetic Model to Support Ophthalmic Suspension Product Development
Maxime Le Merdy1, Ming-Liang Tan1, Andrew Babiskin2
1Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
The AAPS Journal
|January 8, 2020
Summary
Ophthalmic suspensions with undissolved dexamethasone (Dex) increase ocular exposure compared to solutions. Formulation changes like viscosity and strength significantly impact drug exposure, affecting both local efficacy and systemic safety.
Area of Science:
- Pharmacokinetics and Drug Delivery
- Ophthalmology
- Pharmaceutical Sciences
Background:
- Many ophthalmic products utilize suspensions with a high percentage of undissolved active pharmaceutical ingredients (API).
- Understanding the pharmacokinetic implications of suspension formulations is crucial for ocular drug development.
Purpose of the Study:
- To compare ocular and systemic pharmacokinetics of dexamethasone (Dex) in suspension versus solution formulations using an ocular physiologically based pharmacokinetic (O-PBPK) model.
- To assess the impact of formulation strength and viscosity on drug exposure.
Main Methods:
- Utilized a previously rabbit-verified O-PBPK model for dexamethasone.
- Conducted simulations to analyze drug clearance mechanisms and pharmacokinetic profiles.
- Varied formulation parameters including drug strength and viscosity.
Main Results:
- Dexamethasone suspension showed significantly higher aqueous humor and plasma exposure compared to a saturated solution.
- Increased formulation strength led to dose-dependent increases in both ocular and systemic exposure.
- Higher viscosity formulations enhanced ocular absorption without substantially affecting systemic exposure.
Conclusions:
- Solid particles in ophthalmic suspensions can enhance ocular drug exposure but may also increase systemic exposure.
- The O-PBPK model is a valuable tool for correlating formulation changes to both ocular and systemic exposure.
- Consideration of both local efficacy and systemic safety is essential in ophthalmic suspension development.
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