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Cynthia Qian, Kay D Rittenhouse, Thomas Eissing, Samia Ezzine, Todd A Katz, Jean Daniel Arbour; Pharmacokinetic Simulations of Intravitreal Aflibercept and Brolucizumab to Explore Results from Clinical Trials. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4206.
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© ARVO (1962-2015); The Authors (2016-present)
To identify potential explanations for clinical outcomes by simulating vitreous levels of intravitreal (IVT) aflibercept (IVT-AFL) and brolucizumab derived from randomized controlled trial dosing regimens.
Pharmacokinetic (PK) simulations of aflibercept and brolucizumab were conducted using data sources described in Table 1. Multi-dose profiles were developed according to dosing regimens used in OSPREY and HAWK/HARRIER. Thresholds for effective intraocular vascular endothelial growth factor (VEGF) suppression were derived from published studies for IVT-AFL (Table 1) and from modeling brolucizumab.
In the model, vitreous concentrations of IVT brolucizumab peaked higher (Cmax) and declined faster to lower molar concentrations (Cmin) compared with IVT-AFL, consistent with their relative molar doses and estimated half-lives of 4.4–5.1 and 9.1–11 days, respectively, estimated using serum PK for IVT brolucizumab and aqueous PK for IVT-AFL. Brolucizumab vitreous concentrations using OSPREY posology showed wider fluctuation between Cmax and Cmin than IVT-AFL, with Cmin below intraocular VEGF suppression concentrations at time points towards Week 56, where declines in visual acuity (VA) were observed for the IVT brolucizumab group. In contrast, IVT-AFL vitreous concentrations were maintained above the VEGF suppression threshold through to Week 56 where VA maintenance of gains and/or improvement were observed. In HAWK/HARRIER, the reported visual and anatomic outcomes for patients that maintained a 12-week dosing interval are confounded with those that received doses every 8 weeks (up to 62% of patients).
Modeling of IVT-AFL and IVT brolucizumab vitreous concentrations indicated that vitreous half-life largely explains drug durability. The findings based on this PK model might explain, in part, the results from HAWK/HARRIER, where only ~38–46% of patients receiving brolucizumab were maintained on a 12-week dosing regimen through to Week 96. In the second year of the VIEW studies, 48–54% of patients treated with IVT-AFL were on quarterly dosing. In the ALTAIR study, by the end of Year 2, ~60% were treated with ≥12-week IVT-AFL intervals and ~40% reached 16 weeks.
This is a 2020 ARVO Annual Meeting abstract.
Table 1. Data sources for PK simulations
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