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Thomas Eissing, Michael W. Stewart, Cynthia X. Qian, Kay D. Rittenhouse; Durability of VEGF Suppression With Intravitreal Aflibercept and Brolucizumab: Using Pharmacokinetic Modeling to Understand Clinical Outcomes. Trans. Vis. Sci. Tech. 2021;10(4):9. doi: https://doi.org/10.1167/tvst.10.4.9.
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To investigate whether vascular endothelial growth factor (VEGF)–suppression durations contribute to our understanding of clinical trial outcomes by simulating vitreous molar concentrations (Cvm) of intravitreal aflibercept (IVT-AFL) and brolucizumab (IVT-BRO) using pharmacokinetic (PK) modeling.
A PK model simulated Cvm 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.
Cvm peaked higher (Cmax) and decreased more quickly to the VEGF-suppression threshold and minimum (Cmin) 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 Cmax-Cmin fluctuations than IVT-AFL. The IVT-BRO Cmin fell below the VEGF-suppression threshold at timepoints near w56, when decreases in BCVA were also observed. The IVT-AFL vitreous Cmin remained above the suppression threshold through w56, where BCVA gains were maintained.
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.
The PK modeling suggests that more patients may be maintained on ≥q12w dosing with IVT-AFL than with IVT-BRO.
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