Physiologically based ocular pharmacokinetic modeling using computational methods.

By explicitly representing ocular anatomy, computational fluid dynamic simulation methods model drug mass transport both within and between ocular tissue regions, providing reliable animal-to-human translation of bioavailability. Here, we apply physiologically based models to simulate ocular drug administration. A non-anatomical model is used that applies a simple theorem for calculating ocular bioavailability from a topical dose.

Simulating intravitreal injections in anatomically accurate models for rabbit, monkey, and human eyes.

Purpose: To develop models for rabbit, monkey, and human that enable prediction of the clearance after intravitreal (IVT) injections in one species from experimental results obtained in another species.

Methods: Anatomically accurate geometric models were constructed for rabbit, monkey, and human that enabled computational fluid dynamic simulation of clearance of an IVT injected bolus. Models were constructed with and without the retrozonular space of Petit.

Simulating dissolution of intravitreal triamcinolone acetonide suspensions in an anatomically accurate rabbit eye model.

Purpose: A computational fluid dynamics (CFD) study examined the impact of particle size on dissolution rate and residence of intravitreal suspension depots of Triamcinolone Acetonide (TAC).

Methods: A model for the rabbit eye was constructed using insights from high-resolution NMR imaging studies (Sawada 2002). The current model was compared to other published simulations in its ability to predict clearance of various intravitreally injected materials.

In vitro transport and partitioning of AL-4940, active metabolite of angiostatic agent anecortave acetate, in ocular tissues of the posterior segment.

Purpose: The purpose of this study was to evaluate partitioning into and transport across posterior segment tissues (sclera, retinal pigment epithelium (RPE)-choroid) of AL-4940, the active metabolite of angiostatic cortisene anecortave acetate (AL-3789).

Methods: Transport of [(14)C]-AL-4940 was measured through RPE-choroid-sclera (RCS) and sclera, excised from Dutch Belted pigmented rabbits' eyes, in the directions of scleral to vitreal (S-->V) and vitreal to scleral (V-->S) for 3 h at 37 degrees C using Ussing chambers. Tissue integrity was monitored by transepithelial electrical resistance (TEER), potential difference (PD), and biochemical assay (LDH).

Controlled flow-through dissolution methodology: a high-performance system.

Measuring release rates using compendial systems, especially for sparingly soluble compounds, often produces complex results with less than desired precision and lacks relevance to key formulation or biological parameters. A flow-through approach was used by focusing on convective diffusion and controlling certain key physical-chemical factors. Results are presented for an automated multisample flow-through system that displays significant advantages over compendial (1) stirred and (2) flow-through systems.

Impact of density gradients on flow-through dissolution in a cylindrical flow cell.

Measuring release rates for sparingly soluble compounds requires slow flow rates to achieve measurable eluent levels. However, flow rate cannot be reduced indefinitely because density gradients could measurably alter the drug release rate. Finite element simulations of convective diffusion/dissolution with an applied concentration-dependent density gradient reproduced the trends of the changes in dissolution rate on eluent flow rate which occur upon switching flow direction and sample cell orientation relative to gravitational field as observed in the literature employing a rectangular flow cell.

Reexamination of convective diffusion/drug dissolution in a laminar flow channel: accurate prediction of dissolution rate.

Purpose: The convective diffusion/dissolution theory applied to flowthrough dissolution in a laminar channel was reexamined to evaluate how closely it can predict release rate for a model compound on an absolute basis--a comparison that was lacking from the original literature observations reported from this technique.

Methods: The theory was extended to allow for a finite flux of dissolving material, replacing the fixed concentration by a flux condition on the dissolving surface. The derivation introduces a new parameter, k(s), an area-independent analog of the dissolution rate constant defined in the USP intrinsic dissolution procedure.

Dissolution of anecortave acetate in a cylindrical flow cell: re-evaluation of convective diffusion/drug dissolution for sparingly soluble drugs.

Steady-state drug release rates were measured from a model cylindrical implant, comprised mainly of the sparingly soluble drug anecortave acetate, suspended as an obstacle in a cylindrical flow cell. Dissolution medium was delivered at a steady, slow flow rate (0.05-0.

Finite and infinitesimal representations of the vasculature: ocular drug clearance by vascular and hydraulic effects.

New methods are presented for simulating steady-state drug concentration in vitreous, choroid, and sclera from an intravitreal device. Clearance by choroidal flow and intraocular pressure (IOP) -induced Darcy hydraulic flow are included. Two methods are proposed for modeling the vasculature using simple one-dimensional models for simulating drug concentration profiles from intravitreal devices.

Hydraulic flow and vascular clearance influences on intravitreal drug delivery.

Purpose: A recent paper proposed a model for hydraulic flow inthe eye, claiming this could affect intravitreal drug administration. The impact of flow on various modes of administration was investigated in a physiologically accurate ocular model of the rabbit eye.

Methods: Hydraulic flow initiated at the hyaloid was simulated in a three-dimensional finite element model including effects of convection and episcleral efflux.