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Erik L. Nimz, Clinton W. Van't Land, Jaime A. Yáñez, James E. Chastain; Intraocular and systemic pharmacokinetics of brolucizumab (RTH258) in nonhuman primates. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4996.
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© ARVO (1962-2015); The Authors (2016-present)
Brolucizumab, (RTH258, Alcon Research Ltd., a Novartis Company, Fort Worth, TX) is a 26.3 kDa humanized monoclonal single-chain variable domain antibody fragment consisting of 252 amino acids that inhibits human vascular endothelial growth factor A (VEGF-A). Brolucizumab is in clinical development for the treatment of neovascular age-related macular degeneration (nAMD). This study investigated the intraocular and systemic pharmacokinetics of brolucizumab after intravitreal or intravenous injection in nonhuman primates.
A total of 29 cynomolgus monkeys received brolucizumab as either a single bilateral intravitreal dose (1.0 or 6.0 mg/eye; n=9/group) or a single intravenous injection (2.06±0.05 mg/kg; n=11). Brolucizumab concentrations were determined in the vitreous, aqueous humor, retina, retinal pigment epithelium (RPE)/choroid, and serum following intravitreal injection, and in serum alone following intravenous injection using an enzyme-linked immunosorbent assay. Pharmacokinetic parameters were determined by compartmental and noncompartmental methods.
After intravitreal injection, brolucizumab was cleared in parallel from all ocular compartments with a mean terminal half-life of 56.8±7.6 h. It distributed to the retina and RPE/choroid with maximal concentration in the central retina and RPE/choroid being 42% and 18% of that observed in the vitreous, respectively. Maximal serum concentrations were very low (>6000-fold less than those observed in vitreous) and also cleared in parallel with the ocular compartments with a serum half-life of 46.5 h. After intravenous administration, brolucizumab had a terminal half-life in serum of 5.6±1.5 h. The difference in serum half-life following intravitreal and intravenous administrations suggests that clearance from the ocular compartments is the rate-limiting step in the systemic clearance of brolucizumab when administered via intravitreal injection.
This study demonstrates that in nonhuman primates following intravitreal injection, brolucizumab is cleared in parallel from all ocular compartments with a mean half-life of 56.8±7.6 h, while the systemic half-life following intravenous injection is 5.6±1.5 h. Brolucizumab readily penetrates through the retina to reach the RPE/choroid with minimal subsequent systemic exposure, supporting its clinical development for nAMD.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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