CHAPTER 59 Principles of intravitreal application of drugs
Fundamental principles of intravitreal drug delivery
The challenge of treating posterior segment disease resides in the obstacles encountered while trying to achieve therapeutic drug concentrations at the level of the retina and choroid. Topically administered drug that is not lost immediately to the systemic circulation (less than 5% is absorbed into the eye) is absorbed through the cornea into the anterior chamber where it is eliminated through the trabecular meshwork. It achieves an even lower concentration in the vitreous because of the longer diffusion distance as well as the counterdirectional convection current from the ciliary body to the trabecular meshwork. Drugs delivered to the subTenon’s space can penetrate the more permeable sclera to achieve higher concentrations in the retina and choroid. However, the tight junctions of the retinal pigment epithelium (RPE) and choroidal blood flow provide barriers to accessing the retina. Systemically administered (either intravenous or oral) drugs are one avenue to circumvent some of these barriers, especially if the drug is lipophilic and is therefore able to bypass the blood–retinal barrier. The systemic side effects from high enough concentrations of drug required to attain intraocular efficacy, however, limit the utility of many systemically administered drugs1,2. Alternatively, drugs administered intravitreally can attain a high enough concentration for direct treatment of retinal conditions. Drugs delivered intravitreally are eliminated by outflow through either the anterior route, composed of the trabecular meshwork, or the posterior route, through the blood-retinal barrier, into the systemic circulation1,3.
The principles to finding an ideal drug formulation for intravitreal administration require a number of qualifications. The first is that the drug should have a reasonable half-life that does not mandate frequent repeated injections and repeated risk of complications. Anti-VEGF agents require repeated injections because they have short half-lives and first order kinetics (Fig. 59.1A,C)4,5. Intravitreal steroids, such as triamcinolone, are biphasic, or follow a two-compartment model with exponential decline initially, followed by first order kinetics after 1 month (see Fig. 59.1A,B)6. In contrast, sustained-release steroid devices can demonstrate zero order kinetics (flat line shown in Figure 59.1A), releasing a constant amount of therapeutic level steroid for the lifespan of the implant (Fig. 59.1D)7. A second qualification for the ideal intravitreal drug formulation is that administration of the drug should not interfere with the transparency of the ocular media as not to interfere with vision. This comes into play with microsphere and nanosphere technology where the size of the particle can determine the level of visual obscuration after an injection. A third requisite for an intravitreally administered drug is to have the ability to be delivered at a therapeutic dose that does not cause toxicity or impede normal cellular activity3. By providing a constant lower concentration of drug over time (zero order) rather than larger spurts of drug that decrease rapidly (first order), sustained release devices are advantageous in that they provide therapeutic levels of drug without as much local or systemic toxicity.
Sustained release drug delivery platforms now available or under investigation are shown in Figure 59.2. They include devices that are suspended in the vitreous cavity by fixation to the sclera, injected into the suprachoroidal space, or into the vitreous cavity as a free-floating device, placed underneath conjunctiva, or given intrasclerally.
Intravitreal injection of drugs
Special considerations in infants
Pars plana location varies with infant development and can be located 1–1.5 mm behind the limbus in premature infants, but is 2–3.5 mm from the limbus in full-term infants. This affects the approach to needle placement during intravitreal injections8. Accordingly, the vitreous volume in infants is approximately two-thirds to three-fourths the size of adults, thus requiring adjustments in administered drug volume so as not to increase intraocular pressure too severely or cause drug toxicity to the retina.
Drugs used as intravitreal injections
Anti-bacterial
The mainstay of empiric treatment for bacterial endophthalmitis employs the use of ceftazidime, a third generation cephalosporin with increased activity against Gram-negative organisms, and vancomycin, the drug of choice for methicillin-resistant Staphylococcus aureus and other Gram-positive organisms9. Despite the fact that the fourth generation fluoroquinolones have good intravitreal penetration taken systemically, their intravitreal use has not been studied in humans although in rabbits, 625 µg of levofloxacin and 400 µg of gatifloxacin appear to be non toxic, whereas moxifloxacin was benign at doses up to 160 µg10–12. Clindamycin has been used as an intravitreal injection to treat gram positive organisms is penicillin-allergic individuals, anaerobes, and most recently has been given in conjunction with dexamethasone 400 µg intravitreally to treat posterior pole toxoplasmosis chorioretinitis without any evidence of retinal toxicity13 (Table 59.1).
Anti-fungals
Fungal endophthalmitis is most commonly treated with intravitreal amphotericin B, which has been shown to be effective against most Candida species as well as Aspergillus, Rhizopus, and Penicillium. Non-toxic doses up to 10 µg have been shown, although there have been reports of retinal necrosis when injected too close to the retina14. The liposomal formulation of amphotericin B has been shown in animal models to have less toxicity to the retina. A single case of its intravitreal application in a patient with fungal candida endophthalmitis without any evidence of retinal toxicity has been reported15. Among the newer generation triazoles (voriconazole, ravuconazole, posaconazole) that have broad anti-fungal coverage with relatively low toxicity, only voriconazole has been given intravitreally in humans. The short half-life of voriconazole results in the requirement for close observation with frequent repeat injections (Table 59.1). Sen et al. showed in their case series that five patients who had fungal endophthalmitis resistant to fluconazole and amphotericin B responded to intravitreal voriconazole16. Although the echinocandin caspofungin does not appear to reach therapeutic levels in the vitreous when given systemically, this agent shows promise as an intravitreal agent against Candida and Aspergillus. Kusbeci and colleagues demonstrated its effectiveness against C. albicans endophthalmitis in rabbits17,18.
Anti-virals
Aciclovir is an anti-viral that is effective against the herpes family of viruses. It becomes activated in virus-infected cells by a virally encoded enzyme and is therefore non-toxic to uninfected cells. Ganciclovir is a nuceloside analog of aciclovir with 10–100-fold increased activity against cytomegalovirus (CMV). Although rabbit studies show that ganciclovir given intravitreally is non-toxic at doses up to 400 µg, in humans it can be used safely at 2–5 mg even as often as every week19,20. Foscarnet is effective against herpes simplex virus, varicella zoster virus, and CMV. Intravitreal foscarnet can be given intravitreally at a dose of 2.4 mg without causing toxicity (Table 59.1). Cidofovir is a nucleoside analog that has a longer duration of action due to prolonged clearance compared with ganciclovir or foscarnet. However, it causes a high rate of uveitis (26%) and hypotony, although these complications can be prevented by prophylactically treating with probenecid and topical steroid21,22.
Steroids
Triamcinolone acetonide (TA) is a corticosteroid that was first used as an intravitreal injection by Machemer to prevent the development of proliferative vitreoretinopathy after retinal detachment repair23. It now has a variety of uses including the treatment of cystoid macular edema (CME) resulting from uveitis, diabetes, retinal vein occlusions, as well as in pseudophakic CME, radiation maculopathy, and CME related to retinitis pigmentosa (Table 59.2). The use of intravitreal triamcinolone to treat CME as a result of retinal vein occlusion was recently investigated in the SCORE (Standard Care vs. Corticosteroids in the treatment of retinal vein occlusion) studies. These studies demonstrated a significant treatment benefit in patients with central retinal vein occlusions with an odds ratio of attaining the primary outcome (≥15 letters of best corrected visual acuity improvement from baseline) of five-fold over the observation group. By 1 year, the rate of cataract formation was 33%, and 35% required IOP-lowering medication in the 4 mg treatment group (this was significantly higher than the observation group)24. No treatment benefit over standard care was demonstrated for BRVO (where standard treatment was focal or grid laser)25.
