Intravitreal Administration

Intravitreal injection is the most direct approach for delivering drug to the vitreous humor and retina; however, this method of administration has been associated with serious side efects, such as endophthalmitis, cataract, hemorrhage, and retinal detachment (59). In addition, multiple injections are usually required, further increasing the risk. Nevertheless, intravitreal injection continues to be the mode of choice for treatment of acute intraocular therapy.

The kinetic behavior of intravitreally delivered drugs is complicated by the stagnent, nonstirred nature of the normal vitreous. Mechanisms that may influence movement of molecules within the vitreous include diffusion, hydrostatic pressure, osmotic pressure, convective flow, and active transport (70). For small to moderately sized molecules, such as fluorescein or dex-tran, diffusion is the predominant mechanism of transvitreal movement (4,70). Although low-level convective flow has been observed within the vitreous (71), this flow has only a negligible effect on transvitreal movement in comparison to diffusion. For small to moderately sized molecules, diffusion within the vitreous is generally unimpeded and similar to that observed in water or saline (4,70).

1. Distribution and Elimination

As shown in Figure 8, drug distribution and elimination can occur in two main patterns: diffusion from the lens region toward the retina with elimination via the retina-choroid-sclera or anterior diffusion with elimination via the hyloid membrane and posterior chamber (4). A molecule's path of distribution and elimination in the vitreous largely depends on its physio-chemical properties and substrate affinity for active transport mechanisms in the retina. Lipophilic compounds, such as fluorescein (72) or dexamethasone (73), and transported compounds tend to exit mainly via the retina. On the other hand, hydrophilic substances, such as fluorescein glucuronide, and compounds with poor retinal permeability, such as fluorescein dextran, diffuse primarily through the hyloid membrane into the posterior chamber and eventually into the anterior chamber (72). Table 9 shows vitreal half-lives for a variety of drugs and eye conditions. Generally, shorter half-lives are

Figure 8 Schematic of exit pathways from the vitreous humor: (a) transretinal, (b) by way of drainage out of the aqueous humor; (c) compartmental model showing kinetic relationships between a, anterior chamber, p, plasma, and v, vitreous. (Reprinted with permission from Maurice, D. M. and Mishima, S. (1984). Ocular pharmacokinetics. In: Pharmacology of the Eye (M. L. Sears, ed.). Springer-Verlag, Berlin, p. 73.) (Ref. 4).

Figure 8 Schematic of exit pathways from the vitreous humor: (a) transretinal, (b) by way of drainage out of the aqueous humor; (c) compartmental model showing kinetic relationships between a, anterior chamber, p, plasma, and v, vitreous. (Reprinted with permission from Maurice, D. M. and Mishima, S. (1984). Ocular pharmacokinetics. In: Pharmacology of the Eye (M. L. Sears, ed.). Springer-Verlag, Berlin, p. 73.) (Ref. 4).

associated with elimination through the retina, with its high surface area, while longer half-lives are reflective of elimination through the hyloid membrane and the anterior segment.

Injection volume and position within the vitreous body can also influence the distribution and elimination pattern of a drug. Friedrich et al. demonstrated that these factors had a substantial effect on vitreal distribution and elimination of fluorescein and fluorescein glucuronide (74). Four extreme positions and injection volumes of 15 or 100 mL were considered. The mean concentration of drug remaining in the vitreous 24 hours postdose varied by up to 3.8-fold depending on injection position, and increasing injection volume dampened this effect.

Retinal inflammation (which can cause a breakdown of the blood-retinal barrier) and aphakia are common pathophysiological states that can alter a drug's vitreal kinetics. Friedrich et al. showed that drug diffu-

Table 9 Vitreous Humor Half-Lives of Drugs Administered Intravitreally

Drug

Species

Half-Life (h)

Ref.

ISIS 2922a

Rabbit

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