Abstract
Purpose :
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.
Methods :
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.
Results :
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.
Conclusions :
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.