Classical Modeling Approaches

Initially, a classical pharmacokinetic approach is applied to concentration-time curves derived from topical instillation to the eye in much the same manner as data derived from systemically administered drugs. The curve is first expressed by a computer-determined sum of exponentials, which closely fit the experimental data and likewise show no systemic deviation. In the eye, aqueous humor is most often assigned to the central compartment, which is reversibly connected to one or more peripheral compartments and/or a reservoir compartment in the various models (or schemes) that have been derived. This choice is compatible with physiological reality since aqueous humor, which fills the anterior and posterior chambers, is the circulating fluid bathing the peripheral tissues. Drugs instilled topically on the eye primarily reach the first third of the eye, which encompasses these regions. Topically applied ophthalmic drugs do not reach the retina in significant concentrations. Consequently, models can be devised that treat the viscous region as a central compartment particularly when drug is administered intravitreally.

In the eye, the cornea, conjunctiva, lens, iris/ciliary body, choroid, and vitreous are specific tissues that are often lumped together into one or more peripheral compartments. A peripheral compartment can be reversibly connected to a central compartment, but if redistribution into aqueous humor is negligible or nonexistent, peripheral tissues can act as a sink or reservoir compartment. The exit out of the eye is into the blood or circulating fluid of the body.

Figure 3 lists the classical compartmental schemes most commonly applied to ophthalmic drugs following topical application. For many years pilocarpine received the most attention (35,44-47). More recently, publications focusing on classical modeling have decreased, but those that have been published used a varied assortment of drugs for study (5,19,22,36,40,48-51). The most appropriate model seems to depend heavily on the design of the study (i.e., number and length of sampling periods and number of tissues measured for drug content over time), the specificity and sensitivity of the assay, the sophistication of the curve-fitting routine used to analyze the data, and the likelihood that the data can be interpreted by a complex modeling scheme. When aqueous humor or vitreous concentrations of drug are measured over time, either mono- or biexponential equations adequately describe the disposition of drug (5,13,14,22,49-51).

Since it is relatively easy to remove cornea, conjunctiva, lens, iris/ ciliary body, and/or choroid tissues along with aqueous humor, the assignment of barriers and peripheral and/or reservoir compartments is not particularly difficult with the exception of the cornea. Although the cornea is clearly a physical barier to drug entry into the anterior chamber, it is actually divided into three significant kinetic barriers: the multilayered lipophilic epithelium, the aqueous-like stroma, and the single-celled lipophilic endothelium. The specific corneal permeability rate for each

Figure 3 Classic pharmacokinetic schemes used to express compartmentalization for topically applied ophthalmic drugs. PC = precorneal area; EP = corneal epithelium; AH = aqueous humor; P = peripheral or intraocular tissues accessible from aqueous humor; ST/AH = stroma, endothelium and aqueous humor (i.e., kinetic homogeneity), RE = reservoir (i.e., blood and systemic fluids).

Figure 3 Classic pharmacokinetic schemes used to express compartmentalization for topically applied ophthalmic drugs. PC = precorneal area; EP = corneal epithelium; AH = aqueous humor; P = peripheral or intraocular tissues accessible from aqueous humor; ST/AH = stroma, endothelium and aqueous humor (i.e., kinetic homogeneity), RE = reservoir (i.e., blood and systemic fluids).

drug depends on the drug's partitioning properties and molecular weight relative to the individual properties of each barrier (56-62). The sum of the resistances of each layer represents the apparent corneal permeability rate. However, for pilocarpine a closer study of its kinetics in each barrier by Lee and Robinson (44) indicated that the stroma and endothelium could be more correctly associated with the aqueous humor compartment, and only the corneal epithelium was a barrier for entry of drug into the anterior chamber. Although the endothelium is lipophilic, it is only one cell thick and is apparently not as significant a barrier as the much thicker, more tortuous epithelium with 9 or 10 layers.

This latter division of corneal layers into a single epithelial barrier and the assignment of stroma and endothelium into a compartment along with aqueous humor may be correct not only for pilocarpine, but also for other hydrophilic drugs for which the epithelium is the major significant barrier. Water-soluble drugs of relatively small molecular weight (<500-900) likely penetrate the epithelium predominantly by paracellular pathways (30,53). Consequently, as long as the drug is soluble, a high topical concentration can be applied tot he cornea to promote a high penetration rate and overcome poor penetrability.

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