Vitreous VEGF Clearance Is Increased after Vitrectomy

Abstract

Purpose. Pars plana vitrectomy (PPV) has been reported to reduce macular thickness and improve visual acuity in patients with diabetic macular edema (ME). The hypothesis for the study was that after PPV, clearance is accelerated and VEGF concentrations are reduced. To test this hypothesis, hVEGF(165) injections were performed in rabbit eyes, with and without PPV, and vitreous VEGF levels were measured as a function of time. Methods. The PPV group rabbits had a bilateral 25-gauge PPV, and in the no-PPV group, rabbits had intact vitreous. Intravitreal injections of hVEGF(165) were performed, and the animals were euthanatized at time points up to 7 days. The vitreous was isolated and an enzyme-linked immunosorbent assay was used to measure the VEGF levels. Pharmacokinetic parameters were determined in a noncompartmental analysis approach. Results. Mean vitreous VEGF levels decreased more rapidly in eyes subjected to PPV than in no-PPV eyes. The vitreous VEGF half-life (t([)(1/2)(])) in PPV eyes was 10 times shorter than that in normal eyes. In addition, mean clearance and mean area under the curve (AUC) increased and decreased, respectively, in eyes that underwent PPV. Conclusions. VEGF clearance is increased after PPV. Reducing VEGF concentrations in the vitreous post-PPV may partially explain the improvement in macular thickness in some patients with ME. Unexpectedly, the half-life of VEGF in the vitreous, even in no-PPV eyes, was <3 hours, whereas compounds of similar molecular weight typically have longer vitreous half-lives. The back of the eye may be uniquely adapted with rapid-clearance mechanisms to regulate vitreous VEGF levels. Further study is suggested.

Pharmacokinetics of Intravitreally Injected Bevacizumab in Vitrectomized Eyes

“…11 However, there are several concerns with regard to their experiment. Although the molecular weight of hVEGF165 is 42 kDa, equivalent to the size of ranibizumab (48 kDa), the vitreous half-life was 2.46 h, which was far shorter compared to that of ranibizumab (2.88 days) 18 or even that of a very small molecule such as vancomycin (2.6 days, molecular weight 1449.3 Da).…”

“…Up to now, based on past animal studies and some supportive clinical evidence, drug clearance has been generally assumed to increase and clinical drug effectiveness decrease, in vitrectomized eyes. [10][11][12][13][14][15] However, there is scarce data on the PK of intravitreally injected bevacizumab in vitrectomy only (without lensectomy) eyes and scant evidence to ascertain the most effective dosing schedule for IVB injection in vitrectomized eyes. 16 Hence, this study was performed to comparatively analyze the PK profiles of intravitreally injected bevacizumab in vitrectomized (V) eyes versus nonvitrectomized control (C) eyes and to ultimately suggest the most adequate treatment regimen for IVB injection in vitrectomized patients.…”

Antiangiogenic Shift in Vitreous after Vitrectomy in Patients with Proliferative Diabetic Retinopathy

“…Our findings are consistent with a recent report by Lee et al that VEGF is cleared more rapidly in vitrectomized rabbit eyes. 11 In contrast, the level of endostatin did not decrease significantly after the initial vitrectomy, further supporting the notion that the rate of clearance of molecules in vitrectomized eyes is different for different types of molecules in the vitreous.…”

“…10 Moreover, it was demonstrated recently that the clearance of VEGF from the vitreous is increased after vitrectomy in a rabbit model. 11 However, to the best of our knowledge, there have not been studies on the clearance of VEGF and erythropoietin in human eyes.…”

Pars Plana Vitrectomy for Diabetic Macular Edema

“…30 Therefore, following PPV, VEGF and other pro-inflammatory cytokines would be expected to diffuse away from the macula more easily. 31 Conversely, the post-vitrectomy decrease in the viscosity of the vitreous cavity has the possible disadvantage of interfering with intraocular pharmacokinetics and reducing the half-life of intravitreal drugs. 32 In the absence of large RCTs of PPV for DME we aimed to undertake a systematic review and meta-analysis to assess if PPV is an appropriate surgical intervention.…”