Transient analysis of ocular drug delivery: zero-volume effect

Area of Science:

• Ophthalmology
• Pharmaceutics
• Mathematical Modeling

Background:

• Ophthalmic drug delivery faces challenges with premature precorneal drainage, leading to nonproductive drug loss.
• Dose volume reduction (DVR) is a strategy to improve drug bioavailability by minimizing this loss.
• Previous models for DVR bioavailability enhancement relied on steady-state assumptions.

Purpose of the Study:

• To introduce a novel mathematical method for calculating bioavailability enhancement via DVR.
• To evaluate the impact of transient effects on DVR bioavailability, challenging previous steady-state assumptions.
• To identify drug physicochemical properties influencing the effectiveness of DVR.

Main Methods:

• Development of a new mathematical model to calculate bioavailability enhancement.
• Inclusion of transient effects, distribution coefficients, and diffusion coefficients in the model.
• Analysis of the influence of drug lipophilicity and permeability on the zero-volume effect.

Main Results:

• The new model indicates that steady-state assumptions in prior studies may overestimate bioavailability enhancement.
• Transient effects significantly influence the calculated bioavailability enhancement.
• For large, lipophilic molecules (high distribution, low permeability), transient effects can negate the zero-volume effect.

Conclusions:

• A refined mathematical approach is necessary for accurately predicting DVR bioavailability enhancement.
• Transient effects are critical and can substantially alter bioavailability outcomes, especially for lipophilic drugs.
• The findings necessitate a re-evaluation of DVR efficacy based on specific drug properties and dynamic physiological processes.