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Robert L Avery, Alessandro Castellarin, Nathan Steinle, Dilsher Dhoot, Dante Joseph Pieramici, Robert F See, Stephen Couvillion, Ma Nasir, Kha Le, Jennifer Visich; Systemic Pharmacokinetics Following Intravitreal Injections of Ranibizumab, Bevacizumab or Aflibercept in Patients with DME. Invest. Ophthalmol. Vis. Sci. 2014;55(13):586.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the systemic pharmacokinetics (PK) of the anti-vascular endothelial growth factor (VEGF) therapies, intravitreal (IVT) ranibizumab (RBZ), IVT bevacizumab (BEV) and IVT aflibercept (AFB). Plasma free-VEGF concentrations in patients with diabetic macula edema (DME) were also examined and compared.
Study included 45 patients with DME, with 15 patients assigned to each anti-VEGF agent. All patients were naïve to anti-VEGF therapy or had not received anti-VEGF therapy during the previous 4 months. Each participant received 3 monthly IVT injections of RBZ 0.3 mg, BEV 1.25 mg, or AFB 2.0 mg. Enzyme-linked immunosorbent assays (ELISA) were used to measure anti-VEGF agent concentrations in serum samples collected at screening, 3 hours, 1, 3, 7 and 28 days following the first and third doses. Outcome measures also included plasma free-VEGF levels, as measured by a commercially available human VEGF immunoassay.
Systemic exposure of RBZ was similar between the first and third doses, while that of BEV following the third dose increased by 35% compared with the first dose. Also, systemic exposure of BEV was significantly higher than that of RBZ (Geometric mean AUC ratios ranged 46-67x). While systemic concentration of RBZ remained below its IC50 (0.06 nM) at most observed time points, mean systemic levels of BEV were above its IC50 (0.668 nM) on days 1, 3 and 7 following the third dose. In agreement with the low systemic concentrations of the anti-VEGF agents, levels of free VEGF in plasma remained essentially unchanged throughout the treatment period with RBZ IVT injections, while measured plasma free-VEGF was substantially lower than baseline following both first and third doses of IVT BEV. Systemic exposure data for AFB in DME patients will also be presented.
Systemic RBZ concentrations remained below its IC50 at most observed time points and had minimal effect on systemic free VEGF levels. However, those of BEV following IVT injection reached levels greater than the reported IC50 value for VEGF inhibition at several time points after the third dose and resulted in substantial decreases in systemic free VEGF levels compared to baseline. These observations may provide a rationale for the previously reported differences in systemic serious adverse events reported between these anti-VEGF agents.
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