As in-office treatment paradigms for retinal diseases have increasingly utilized intravitreal corticosteroids and anti-vascular endothelial growth factor (anti-VEGF) agents for a variety of retinal diseases, it is well known that vitrectomy can increase clearance of the pharmaceutical agent, and, in some cases, reduce treatment efficacy. In a similar mechanism of action, we hypothesized that vitrectomy can also enhance clearance of VEGF, leading to an improvement in macular edema. To test this hypothesis, hVEGF165 injections were performed in rabbit eyes with and without pars plana vitrectomy (PPV).1 Animals were euthanized at time points up to 7 days, and the vitreous was isolated. An enzyme-linked immunosorbent assay was used to measure VEGF levels, and pharmacokinetic parameters were determined using a noncompartmental analysis approach (WinNonlin Pro Version 5.2; Pharsight, St. Louis, MO). Results demonstrated that the mean vitreous VEGF levels decreased more rapidly in eyes submitted to vitrectomy compared with nonvitrectomized eyes. Vitreous VEGF half lives (T1/2) of vitrectomized eyes were approximately tenfold shorter than normal eyes, and we concluded that VEGF clearance is increased following PPV (Figure 1).
CLINICAL IMPLICATIONS
The seminal paper in 1994 by Aiello et al2 demonstrated
that increased VEGF levels in the eye correlated
with severity of retinal disease, with the highest levels
seen in patients with ischemic central retinal vein occlusion
(CRVO). The assumption is that with progressive
retinal ischemia there is greater VEGF production in the
eye and worsening of retinal complications such as neovascularization
and macular edema. Conversely, with a
reduction of VEGF levels in the eye, retinal complications
may be reduced, as is evident when patients with
proliferative diabetic retinopathy receive panretinal
photocoagulation (PRP). The PRP results in involution
of the neovascular process and, in some cases, improves
macular edema.
Interspecies scaling methods can be used to predict human postvitrectomy vitreous VEGF concentrations from rabbit data generated in this study. Assuming the VEGF production rate for various disease states is the same for vitrectomized and nonvitrectomized eyes, and that measured human vitreous VEGF specimens were in an approximate steady state, the post-PPV VEGF concentration can be estimated by Css = I/Cl, where Css is the steady state VEGF concentration, I is the VEGF production rate, and Cl is VEGF clearance rate. The mathematical modeling predicts that with increased clearance of VEGF, the retinal disease may progress to a less severe phenotype. For example, although the vitreous VEGF concentration of a nonvitrectomized diabetic patient with active proliferative retinopathy is 2.6 ng/mL2, after vitrectomy the VEGF concentration is predicted to decrease to 0.59 ng/mL, which is representative of the VEGF concentration in quiescent proliferative retinopathy.2
Reducing VEGF concentrations in the vitreous after vitrectomy may partially explain the improvement in macular thickness in some patients with macular edema. Unfortunately, vitrectomy can also increase the clearance of pharmaceutical agents injected into the vitreous; thus, vitrectomy can be viewed as a doubleedged sword for patients with macular edema. It has been reported that intravitreally injected triamcinolone acetonide levels, as interpreted from aqueous humor drug sampling, are cleared from the vitreous faster in vitrectomized eyes.3 Likewise, large-molecular-weight anti-VEGF compounds have been reported to have greater effect on visual acuity in nonvitrectomized eyes compared with vitrectomized eyes, which is likely due to faster elimination of drug in vitrectomized eyes.4 A potential strategy to overcome the increased drug clearance in vitrectomized eyes is the use of a sustainedrelease biodegradable implant. The ocular pharmacokinetics of the implant may not be altered in vitrectomized eyes, and encouraging results have been observed in clinical studies.5
CONCLUSION
Vitrectomy for treatment of macular edema has both
positive and negative effects. Although vitrectomy reduces
VEGF by increasing VEGF elimination, the increased elimination
also clears pharmaceutical agents from the vitreous
more rapidly, yielding less effective pharmaceutical treatment
results. Novel approaches to postvitrectomy pharmaceutical
treatments using sustained-release formulations
may be beneficial.
Susan S. Lee, MS, is an employee of Allergan, Inc., Irvine, CA, and the Department of Biomedical Engineering, University of Southern California, Los Angeles.
Michael R. Robinson, MD, is an employee of Allergan, Inc.
_1773249222.png?auto=compress,format&w=75)
