Bevacizumab (Avastin) for retinopathy of prematurity: wrong dose, wrong drug, or both?

I nterest in and controversy over the use of bevacizumab (Avastin; Genentech/Roche, South San Francisco, CA) for the treatment of retinopathy of prematurity (ROP) have increased dramatically after the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) study. Off-label bevacizumab has been used extensively for age-related macular degeneration (AMD) for more than 6 years, and recently the Comparison of AMD Treatments Trials showed it to have similar safety and efficacy to ranibizumab (Lucentis; Genentech/Roche, South San Francisco, CA) in this population. There was, however, an increased incidence of systemic adverse events scattered across many organ systems in the bevacizumab arm of this study, the significance of which remains unclear. There are pharmacokinetic differences between these two vascular endothelial growth factor (VEGF) inhibitors that may be important in at-risk populations such as infants with ROP undergoing organogenesis. In adults the intrinsic serum elimination half-life of ranibizumab is approximately 2 hours, whereas that of bevacizumab is approximately 20 days because it is a full-length antibody with an Fc domain that binds Fc receptors on endothelial cells and reduces systemic clearance. The systemic pharmacokinetics of both ranibizumab and bevacizumab in children is unknown but could be longer. Early in the use of bevacizumab for proliferative diabetic retinopathy (DR), we noted a reduction in leakage of neovascularization in the contralateral, uninjected fellow eye, a finding that raised concern about systemic levels capable of therapeutic effects. This observation prompted us to evaluate lower doses of intravitreal bevacizumab, and we showed reduction in neovascularization even when injecting a dose 200-fold below the typical dose (6.25 mg instead of 1.25 mg). There was initial skepticism as to the causality of fellow eye effects, but these effects have now been observed after bevacizumab injection in DR, vein occlusion, and uveitic cystoid macular edema (CME). One recent report even demonstrated the resolution of CME and retinal neovascularization in the