Intravitreal administration

A Bochot, P Couvreur, E Fattal. Intravitreal administration of antisense oligonucleotides potential of liposomal delivery. Prog Retin Eye Res 19(2) 131—147, 2000. 

Pharmacokinetics Human pharmacokinetics data are limited. Based on preclinical data, it is slowly absorbed into systemic circulation from the eye after intravitreous administration. Metabolized by endo- and exonucleases. Excreted in urine. Half-life 10 days (plasma). 

Intravenous cidofovir is effective for the treatment of CMV retinitis and is used experimentally to treat adenovirus infections. Intravenous cidofovir must be administered with high-dose probenecid (2 g at 3 hours before the infusion and 1 g at 2 and 8 hours after), which blocks active tubular secretion and decreases nephrotoxicity. Cidofovir dosage must be adjusted for alterations in the calculated creatinine clearance or for the presence of urine protein before each infusion, and aggressive adjunctive hydration is required. Initiation of cidofovir therapy is contraindicated in patients with existing renal insufficiency. Direct intravitreal administration of cidofovir is not recommended because of ocular toxicity. 

The drug is slowly cleared from vitreous with a half-life of approximately 55 hours in humans and is subsequently cleared from the retina. Measurable concentrations of drug are not detected in the systemic circulation following intravitreal administration. Immediate therapy of CMV retinitis with fomivirsen was more effective in delaying progression than deferred treatment in a recent clinical trial. Concurrent systemic anti-CMV therapy is recommended to protect against extraocular and contralateral retinal CMV disease. Potential side effects include iritis and vitreitis as well as increased intraocular pressure and changes in vision. An interval of at least 2-4 weeks is recommended between cidofovir administration and use of fomivirsen because of the risk of ocular inflammation. 

This hypothesis is further supported by studies reporting that intravitreous administration of IGF-I or BDNF prevents RGCs death in axotomized eye by activating Akt (Klocker et al., 2000 Nakazawa et al., 2002) and treatment with PI3-K inhibitors increases the loss of RGCs after optic nerve clamping (Nakazawa et al., 2003) and IOP elevation (Huang et al., 2008). 

Bochot, A., Couvreur, P., and Fattal, E. (2000), Intravitreal administration of antisense oligonucleotides Potential of liposomal delivery, Prog. Retin. Eye Res., 19, 131-147. 

Hydrophilic drugs, such as gentamicin, do not cross the blood-retinal barrier readily after systemic administration. After intravitreal administration they have a prolonged half-life of 24 hours or more in the vitreous humor.Their major route of exit is across the lens zonules and into the aqueous humor and then through the aqueous outflow pathways. For the vitreous to act as a depot for these drugs, the agents must be injected, introduced by iontophoresis, or slowly released by a surgically implanted intraocular device. 

Various colloidal systems have been studied for use as potential ophthalmic delivery systems, including liposomes and nanoparticles. Liposomes are bioerodible and biocompatible systems consisting of microscopic vesicles composed of lipid bilayers surrounding aqueous compartments. Liposomes have demonstrated prolonged drug effect at the site of action but with reduced toxicity. Ophthalmic studies have included topical, subconjunctival, and intravitreal administration, but no commercial preparations are currently available for ophthalmic use. 

Retinal damage in the farm of macular inferction has occurred after intravitreal administration of gentamicin. Because amikacin is less toxic when injected intravitreally, the current recommendation far treatment of postoperative endophthalmitis is intravitreal amikacin (or ceftazidime) for gram-negative coverage. 

Mordenti J, Cuthbertson RA, Ferrara N, et al. Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 1251-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. Toxicol Pathol 1999 27 536. 

Roy S, Zhang K, Roth T, Vinogradov S, Kao RS, Kabanov A (1999) Reduction of fibronectin expression by intravitreal administration of antisense oligonucleotides. Nat Biotechnol 17 476 79. 

Two cases of iritis shortly after intravenous administration of cidofovir have been reported (4). Intravitreal administration of cidofovir delays the progression of CMV retinitis, but can be associated with reduced intraocular pressure or vitreitis (5). In two cases the drug association with the iritis was demonstrated by withdrawal and rechaUenge (6). These patients had also taken probenecid, but it is not clear whether or not that was involved. The evidence is that in such cases the cidofovir should be withdrawn treatment should be with a mydriatic and glucocorticoids. 

Fomivirsen (ISIS 2922) is an antisense oligonucleotide that specifically inhibits replication of hnman cytomega-lovirns. It has been developed for intravitreal administration to treat cjdomegalovims retinitis in patients with AIDS. 

Pharmacodynamics. The pharmacokinetics of intravitreal pegaptanib sodium has been evaluated in several preclinical models. Examination of the plasma and vitreous humor concentration data following intravitreal administration of pegaptanib... 

O Neill CA, Christian B, Murphy CJ, et al. Safety evaluation of intravitreal administration of Lucentis in cynomolgus monkeys for 3 months. Invest Ophthalmol Vis Sci 2000 41 S142 (Abstract 732). 

Baum J, Peyman GA, Barza M. Intravitreal administration of antibiotic in the treatment of bacterial endophthalmitis. III. Consensus. Surv Ophthalmol 1982 26 204—206. 

Ferencz JR, Assia El, Diamantstein L, Rubinstein E. Vancomycin concentration in the vitreous after intravenous and intravitreal administration for postoperative endophthalmitis. Arch Ophthalmol 1999 117 1023-1027. 

Viral retinitis may be caused by herpes simplex virus, cytomegalovirus (CMV), adenovirus, and varicella zoster virus. With the highly active antiretroviral therapy (see Chapter 50), CMV retinitis does not appear to progress when specific anti-CMV therapy is discontinued, but some patients develop an immune recovery uveitis. Treatment usually involves long-term parenteral administration of antiviral drugs. Intravitreal administration of ganciclovir has been found to be an effective... 

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