September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Intraocular and systemic pharmacokinetics of brolucizumab (RTH258) in nonhuman primates
Author Affiliations & Notes
  • Erik L. Nimz
    Ocular PKD, Alcon Research, Ltd., Fort Worth, Texas, United States
  • Clinton W. Van't Land
    Ocular PKD, Alcon Research, Ltd., Fort Worth, Texas, United States
  • Jaime A. Yáñez
    Merial Limited, North Brunswick, New Jersey, United States
  • James E. Chastain
    Ocular PKD, Alcon Research, Ltd., Fort Worth, Texas, United States
  • Footnotes
    Commercial Relationships   Erik Nimz, Alcon Research, Ltd (E), Novartis (E); Clinton Van't Land, Alcon Research, Ltd. (E), Novartis (E); Jaime Yáñez, Novartis (I); James Chastain, Alcon Research, Ltd. (E), Novartis (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4996. doi:
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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)

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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.

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