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Nardos Tassew, Vladimir Bantseev, Aija McKenzie, Roxanne Andaya, Debbie O'Connor, Daniel Sheinson, Carol A Rasmussen, T Michael Nork, Tim Streit, Helen S Booler, Florence Lorget; The Presence of Protein in Formulation Ameliorates Retinal Changes Observed on OCT Following Intravitreal Administration of Hyperosmotic Solution in Cynomolgus Monkeys. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5828.
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© ARVO (1962-2015); The Authors (2016-present)
Intravitreal injections of hyperosmotic solutions are reported to cause retinal detachments in both rabbits and monkeys, however, the upper limit or the safe osmolality ranges are poorly defined. The effects of osmolality are confounded by formulation, presence/absence of protein and number of injections, which may also produce retinal changes, even when the osmolality is not very high. The aim of this analysis is to assess the impact of osmolality on retinal findings by OCT from a 9 week repeat dose GLP study where a PEGylated anti-Factor D Fab was intravitreally administered in cynomolgus monkeys.
Cynomolgus monkeys were assigned to 4 groups and were dosed intravitreally once every 3 weeks for a total of 4 doses. Groups 1 and 4 (vehicle and high dose drug product (DP); ~407 and 710mOsm/Kg) were administered 2x50ul injections 10 minutes apart, and groups 2 and 3 (low and mid dose DP; ~370 and 710mOsmo/Kg) were administered 50ul injection per eye. The vehicle solution was formulation buffer without protein. OCT imaging was conducted during pre-dose, after first dose, on 2nd day, after the 3rd dose and in recovery phase.
In addition to retinal detachment (RD), 2 novel retinal findings were noted on OCT images: hyper-reflective band (HRB) and hypo-reflective line (HRL). All OCT retinal changes were transient and reversible. Overall, RD incidence was highest in vehicle group and the incidence of all 3 OCT findings was highest in eyes administered 2 injections versus single injection. No RD was observed when high osmolality DP was given as a single injection. Furthermore, there was no correlation between osmolality and whether an eye was more likely to get a certain type of retinal change when the number of injections was factored in.
Osmolality alone was not a factor, and a combination of procedure and presence/absence of protein are likely the causes for the OCT retinal changes in the tested osmolality ranges. Furthermore, the vehicle had the worst outcome suggesting that presence of protein may have a protective effect on RD, HRL. Thus, care must be taken when selecting a vehicle as a control in intravitreal studies, and oncotic pressure of formulation/DP should be considered, rather than osmolality alone.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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