Durability of VEGF Suppression With Intravitreal Aflibercept and Brolucizumab: Using Pharmacokinetic Modeling to Understand Clinical Outcomes

Abstract

To investigate whether vascular endothelial growth factor (VEGF)suppression durations contribute to our understanding of clinical trial outcomes by simulating vitreous molar concentrations (C vm ) of intravitreal aflibercept (IVT-AFL) and brolucizumab (IVT-BRO) using pharmacokinetic (PK) modeling.Methods: A PK model simulated C vm after single-dose IVT-AFL, IVT-BRO, and ranibizumab (IVT-RAN), and extrapolated intraocular VEGF-suppression thresholds and durations. Vitreous PK after multidose regimens used in studies of IVT-AFL versus IVT-BRO were simulated and compared with best-corrected visual acuity (BCVA) data.Results: C vm peaked higher (C max ) and decreased more quickly to the VEGF-suppression threshold and minimum (C min ) levels with IVT-BRO than with IVT-AFL, consistent with their molar doses calculated using molecular weights and vitreous half-lives (26 kDa and 115 kDa; 4.4-5.1 and 9.1-11 days, respectively). The mean VEGF suppression durations were 71 days for IVT-AFL 2 mg and 51 (48-59) days for IVT-BRO 6 mg. Based on dosing in OSPREY (matched dosing to week [w]32 for both agents; thereafter, IVT-AFL every eight weeks [q8w] and IVT-BRO q12w for the last two doses [w32→w44 and w44→w56]), IVT-BRO showed wider C max -C min fluctuations than IVT-AFL. The IVT-BRO C min fell below the VEGF-suppression threshold at timepoints near w56, when decreases in BCVA were also observed. The IVT-AFL vitreous C min remained above the suppression threshold through w56, where BCVA gains were maintained. Conclusions:The PK-modeled mean VEGF-suppression duration for IVT-BRO was substantially shorter than that published for IVT-AFL and may not be sufficient to effectively suppress VEGF throughout q12w dosing.Translational Relevance: The PK modeling suggests that more patients may be maintained on ≥q12w dosing with IVT-AFL than with IVT-BRO.

The Effectiveness of Brolucizumab and Aflibercept in Patients with Neovascular Age-Related Macular Degeneration

“…The stress level amongst patients with nAMD with a visual acuity of 20/200 is comparable to that felt by patients with human immunodeficiency virus and melanoma [ 48 ]. In the context of previous findings [ 41 , 42 , 43 , 44 ], as well as the preliminary observations described in this study, it is worth paying attention to the study conducted by Fernandes et al [ 49 ], who indicate that the low molar mass of brolucizumab, compared to the two aforementioned inhibitors, is the factor which conditions such positive therapeutic effects. This contributes to better penetration of the drug molecule into the tissue, higher local effectiveness, a longer durability of the therapeutic effect, and a lower risk of a systemic side effect occurring, compared with a full-sized immune-globulin G [ 50 ].…”

“…Observations varying from ours were made by Eissing et al [ 44 ], who using mathematical analysis, which in turn, was based on a pharmacodynamic and pharmacokinetic profile, assessed the ability of the three drugs, namely aflibercept, ranibizumab, and brolucizumab, to reduce VEGF concentration. In summation, these authors determined that, considering the average half-life duration of brolucizumab, its use in the case of AMD can be insufficient to inhibit VEGF expression when used every 12 weeks, in comparison to aflibercept [ 44 ].…”

“…Directly after drug administration, VEGF expression is fully inhibited as the drug is administered at a molar concentration greater than that of VEGF [ 45 ]. Thus, as the molar mass of the drug increases, the length of its half-life becomes greater (aflibercept 97–155 kDa > ranibizumab 48 kDa > brolucizumab 26 kDa) [ 44 ]. Moreover, the effectiveness is dependent on the affinity of the inhibitor to VEGF (aflibercept > brolucizumab > ranibizumab) [ 46 ].…”

Choroidal Effusion following Intravitreal Brolucizumab Injection: A Case Report

“…Despite the previous 14 times of anti-VEGF injections (aflibercept, 6 times; ranibizumab, 5 times; and bevacizumab 3 times), he did not experience any ocular inflammation nor choroidal effusion. Using pharmacokinetic modeling, Eissing et al [16] described that the vitreous half-life of brolucizumab was 5.1 days. In our patient, choroidal effusion peaked at 5 days after the injection.…”

“…Using pharmacokinetic modeling, Eissing et al [ 16 ] described that the vitreous half-life of brolucizumab was 5.1 days. In our patient, choroidal effusion peaked at 5 days after the injection.…”