in aphakic vitrectomized eyes than normal eyes during the first 12 hours following injection.

PHARMACOKINETICS OF INTRAVITREAL CRYSTALLINE TRIAMCINOLONE ACETONIDE

After intravitreal TA injections the drug may persist in the vitreous cavity for months. Its clearance also depends on the status of the vitreous as well as the applied dosage and was initially studied in rabbit eyes, reporting disappearance of 0.5 mg TA after 16.8 days in vitrectomized, compared to 41 days in nonvitrectomized, eyes.

Beer and associates determined the anterior-chamber concentration of TA through an anterior-chamber paracentesis after a single 4-mg TA in humans. They calculated a mean half-life elimination of 3.2 days in vitrectomized eyes compared with 18.6 days in nonvitrectomized eyes.25 While the concentration after a single 4-mg dose was maintained at a measurable rate for approximately 3 months, a higher 25-mg dose of TA was sustained at detectable levels for up to 9 months in nonvitrectomized eyes and up to 1.5 years in silicone oil-filled vitreous cavity. An intravitreal injection of 20–25 mg of TA can be present in measurable concentrations during the first 6 months at between 3.0 and 436 µg/l and later at 7–12 months between 0.0 and 11.2 µg/l, respectively. A faster clearance of intravitreal TA in the vitrectomized eye must be considered. The clearance of 0.1 ml (0.3 mg) intravitreal TA after 30 days was 0.22 µg/ml in vitrectomized eyes compared to 0.92 ± 1.25 µg/ ml in nonvitrectomized eyes. Serum levels of TA obtained 4–92 days after an intravitreal high-dose injection of 20–25 mg did not differ significantly (P = 0.174) after the injection (postoperatively: 0.065 ± 0.21 µg/l).

PHARMACOKINETICS OF VEGF

INHIBITORS26–32

It is mandatory for a sufficient treatment of vascular AMD to neutralize the elevated VEGF concentration by suitable concentrations of VEGF inhibitors. If the concentration declines, the choroidal neovascularization progresses, and increased leakage may occur. The permeability of the proliferating vessels accelerates, leading to enhanced leakage of subretinal­ or intraretinal fluid with progression of macular edema and decreased visual acuity. The pharmacokinetics of VEGF inhibitors does not depends neither on age, gender, nor kidney function. An intravitreal injection of 0.5 mg pegaptanib induces a concentration in the vitreous cavity of 350 µg/ml, declining to 1.7 µg/ml within 4 weeks. Studies demonstrated a half-life of pegaptanib by approximately 94 hours in monkeys and 83 hours in rabbits. After monthly injections of 0.5 mg ranibizumab, the highest measured serum concentration was found to be between 0.79 and 2.9 ng/ml and the minimal serum concentration between 0.07 and 0.49 ng/ml. Gaudreault et al. calculated a half-life time of approximately 3 days in rabbit eyes.27 The concentration of ranibizumab in the vitreous cavity is approximately 90 000 times higher than in the blood serum. There is no indication for any metabolism inside the eye.

Bakri et al injected 1.25 mg bevacizumab in the vitreous cavity in rabbits and determined the intravitreal concentration in the vitreous cavity within 30 days.28 The concentration peaked with maximal values (400 µg/ml) 3 days after the injection and declined in an exponential function. The concentration declined by a half-life time of 4.32 days and remained >10 mg/ml in the vitreous cavity during the entire 30 days. However, it remains unknown if the animal model is comparable to humans, who have a three-times bigger vitreous cavity (4.5 versus 1.5 ml).

Beer et al.25 determined the vitreous levels of unbound bevacizumab and unbound VEGF in 2 patients after intravitreal application of bevacizumab. Patient 1 underwent vitrectomy for a retinal detachment 4 weeks after the intravitreal bevacizumab injection. At that time point, the unbound bevacizumab level was 0.16% of the loading dose, a level that was still 3100-fold molar excess of bevacizumab compared to the

measured VEGF levels. In patient 2, who underwent vitreous biopsy for endophthalmitis 48 hours after the injection, the unbound bevacizumab level was 53% of the loading dose, which equaled a more than millionfold molar excess compared to measured intravitreal VEGF levels. VEGF concentration was the lower limit of detection in both patients. The calculated half-life of bevacizumab was approximately 3 days. The authors concluded that a single dose of intravitreal bevacizumab is likely to provide a complete intravitreal VEGF blockade for a minimum of 4 weeks.

In 30 nonvitrectomized eyes with cataract and concurrent macular edema we performed cataract surgery 1–53 days after an intravitreal injection of 1.5 mg bevacizumab. During surgery, a sample from the anterior-chamber fluid was obtained and bevacizumab levels quantified by enzyme-linked immunosorbent assay.29 Concentration of bevacizumab in aqueous humor peaked on the first postinjection day with a mean concentration of 33.3 µg/ml (range 16.6–42.5 µg/ml) and subsequently declined in an exponential fashion. Nonlinear regression analysis determined an elimination half-time of 9.82 days (R2 = 0.81) .

CLINICAL EXPERIENCE AND RESULTS IN VITRECTOMIZED, AIR-FILLED, OR SILICONE OIL EYES

VITRECTOMIZED EYES

There is only limited experience using VEGF inhibitors in vitrectomized eyes due to the exclusion of those eyes from all phase II/III studies. Intravitreal-applied crystalline TA may have a longer effect compared to dissolved drugs, while the concentration of solute bevacizumab seems to decrease more rapidly, leaving only a minor effect at the retina. Intravitreal injections of solute VEGF inhibitors in vitrectomized eyes are therefore currently not recommended.

Silicone oil tamponade

The clinical management of CMV retinitis and associated retinal detachment often involves the concurrent use of silicone oil and ganciclovir (GCV) implants. Perkins et al. investigated the effect of oil tamponade on intravitreal drug levels achieved with a 5-mg GCV implant in rabbits.30 Vitreous GCV levels at days 21 and 42 were similar in both the salineand silicone oil-filled eyes. At day 70, GCV levels were significantly lower in the saline-filled eyes than in silicone-filled eyes. GCV levels may remain for longer in eyes with silicone oil tamponade, supporting the use of combined application.

Silicone oil is also an efficacious delivery system for acetylsalicylic acid in rabbits, extending the duration of the drug in the vitreous cavity.31

A combined 5-FU silicone oil intravitreal tamponade was sustained after a conventional three-port lens-sparing pars plana vitrectomy in porcine eyes in a concentration above 1 µg/ml for 5 days. The pharmacokinetics followed a specific release rate constant of 10.7 µg/cm2.

Gas tamponade

Intravitreal gas bubbles (0.3 ml) in nonvitrectomized eyes may induce a subclinical breakdown of the BRB soon after the gas is absorbed. The effect of intraocular gas tamponade, e.g., perfluoropropane (0.4 ml of 100% C3F8), on intravitreal drug levels was studied for sustained-release fluocinolone (FL)/5-FU 10-mg codrug pellet in white rabbits. On postoperative days 4, 7, 21, and 42, there were no statistically significant differences between FL and 5-FU drug levels in eyes containing C3F8 as compared with control eyes. Therefore, despite an apparent breakdown of the BRB, intraocular gas tamponade seems to have no significant effect on the intravitreal half-life of these drugs. It is therefore suggested that the concentration of intravitreally applied drugs needs no alteration in the presence of intraocular gas.32,33

delivery drug retinal for routes and models Animal • 2 section