Take-home: BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity) was too small to assess the systemic safety of intravitreal anti-VEGF injection for retinopathy of prematurity. Data from pharmacokinetic studies and retrospective clinical studies demonstrate high circulating blood levels and suggest potential effects on neurodevelopment.
BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity) demonstrated the benefit of intravitreal bevacizumab (Avastin, Genentech) to treat stage 3+ retinopathy of prematurity (ROP) in infants with posterior zone I or II disease. The issue of systemic safety remained an unanswered question, however, because of the study’s small size.
Accumulating evidence is cause for concern and underscoring the need for more research evaluating the safety of anti-VEGF injections for ROP, according to Robert L. Avery, MD.
Dr. Avery reviewed findings from the published literature showing that the anti-VEGF agents enter into the bloodstream in physiologically relevant concentrations and have been shown to have pharmacologic effects.
“We know there are fellow eye and distant effects in babies treated with anti-VEGF injections for ROP,” said Dr. Avery, private practice, Santa Barbara, CA. “There (also) is biologic plausibility for adverse effects on lung and neurodevelopment.”
He also presented pharmacokinetics data supporting the theory that ranibizumab (Lucentis, Genentech) may be preferred over bevacizumab from the perspective of systemic safety.
“What is needed is a prospective clinical trial evaluating these therapies,” Dr. Avery added.
Pharmacokinetics of anti-VEGF
Dr. Avery noted that the investigators of BEAT-ROP underestimated the potential systemic risks of bevacizumab therapy, based on an erroneous belief that bevacizumab, as a large molecule, could not penetrate the intact retina or escape the eye except in small amounts.
Dr. Avery mentioned that he and other investigators have shown histologically that bevacizumab penetrates the full thickness retina. He also referenced work by Kong et al who studied infants with ROP and showed that bevacizumab reached a maximum serum concentration of about 1 mcg/mL at about 2 weeks post-intravitreal injection and reduced systemic levels of VEGF for at least 60 days.
“The serum half-life of bevacizumab was about 3 weeks, similar to what we reported in adults treated for age-related macular degeneration, but the maximum serum concentration was about 1 mcg/mL, which is 9 to 10 times higher than what we measured in adults,” Dr. Avery commented.
Similarly, a study by Wu et al found that the serum VEGF concentration in infants was reduced for 2 to 3 months following intravitreal injection with bevacizumab, but not ranibizumab. Hence, bevacizumab has the more potent systemic suppressive effect of the two anti-VEGF agents.