An animal study evaluating the safety of intravitreal antiVEGF agents found no evidence of retinal toxicity with repeat dosing based on electroretinography and histologic evaluation. Retinal penetration and pharmacokinetics were also investigated.
Tel Aviv, Israel-Preclinical studies are providing encouraging findings about the retinal safety of ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin, Genentech) as well as some insight into the pharmacokinetics profiles of these anti-VEGF agents that may help direct their rational clinical use, according to Anat Loewenstein, MD, a co-investigator on the studies.
Results from a series of recent studies performed in an albino rabbit model showed:
"Looking to the future, we hope to conduct additional assays that may provide more quantitative information on retinal penetration, and we believe further studies are warranted to investigate systemic absorption and penetration into the contralateral eye because these issues may have an impact on treatment strategies in the future."
The research represents a joint effort of Israeli and American investigators. Dr. Loewenstein's co-investigators are Shiri Soudri, MD, Gadi Heilweil, MD, Tel Aviv Medical Center and Tel Aviv University; Ido Perlman, PhD, Technion, Haifa; and Geoff Lewis, PhD, and Robert Avery, MD, Santa Barbara, CA.
In a previous, published study, Dr. Loewenstein and colleagues reported lack of retinal toxicity following a single injection of bevacizumab.
Subsequently, a multiple-dose toxicity investigation was undertaken recognizing that in clinical use, anti-VEGF injections are usually given on a repeated basis.
"One concern with intraocular injections of anti-VEGF agents is that VEGF is a survival factor for many cell types, including neuronal and RPE cells. Our multiple-dose studies aimed to identify if there is any cumulative toxicity, including that associated with longer-term VEGF suppression," noted Dr. Loewenstein.
Groups of rabbits received injections of bevacizumab or ranibizumab in one eye and a saline injection as control in the fellow eye. A total of nine injections were administered at 2-week intervals. The animals underwent periodic electroretinography (ERG), and 2 weeks after the last injection, the eyes were enucleated for histologic evaluation.
The ERG curves showed no significant differences between the responses of the control eyes versus either bevacizumab- or ranibizumab-injected eyes. In addition, there was no histologic evidence that either anti-VEGF drug caused retinal toxicity.
"As a caveat, bevacizumab and ranibizumab are antihuman VEGF antibodies. While they have relatively high affinity to rabbit VEGF, their affinity to the animal protein is lower than to human VEGF," noted Dr. Loewenstein.
"To overcome this limitation, the dose of drug we injected was higher than that used clinically," Dr. Loewenstein said. "However, studies are underway investigating the retinal toxicity of antimurine VEGF."
A second study extended previous research on retinal penetration that showed full-thickness penetration after intravitreal injection of a relatively large dose of bevacizumab, 2.5 mg, in rabbit eyes. The current study compared ranibizumab and bevacizumab and aimed to investigate clinically relevant doses. The rabbits received intravitreal injections of 500 µg bevacizumab or 200 µg ranibizumab, and groups of animals underwent enucleation at 1, 3, 7, 14, and 28 days.