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

PURPOSE: 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.