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Mitalee Tamhane, Swati Gupta, Mayssa Attar; Evaluation of vitreous half-life and ocular distribution in rats, rabbits and monkeys after intravitreal administration of a novel biologic. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):221. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Intravitreal administration of biologics offers specific and targeted treatment for retinal diseases. Rabbits and monkeys are commonly used to evaluate ocular pharmacokinetic profiles due to the large vitreous volume and comparability to the human eye, while pharmacodynamic models often use smaller rodent species, such as rats, to minimize API use in early stages. In order to understand the cross-species differences, drug distribution and pharmacokinetics of a biologic (MW-45 KD) was evaluated in rats, rabbits, and monkeys.
Rats, rabbits and monkeys (2-3 animals/timepoint) received a bilateral intravitreal injection of the biologic. Rats received 50 µg/eye (5 µL) and rabbits and monkeys received 1 mg/eye (50 µL). The injection volume was optimized based on the vitreous volume ( 20 µL in rats, 1.5 mL in rabbits and 2 mL in monkey). At designated timepoints, serum, aqueous humor (AH) and vitreous (V) were collected. Concentrations of the drug were measured using qualified enzyme-linked immunosorbant assay (ELISA) method.
The vitreous half-life in rats, rabbits and monkeys was approximately 1, 5 and 2 days respectively. The drug exposure in ocular matrices and serum across all species followed a consistent pattern as follows: Vitreous > Aqueous humor > Serum. In the rat and rabbit, the concentrations in AH were at least 10 fold lower than those in vitreous, where as in monkey, the difference was 2 to 4 fold. In serum, concentrations were at least 100 fold lower than the vitreous across all species. The pharmacokinetic parameters are summarized in Table 1.
Based on the observed vitreous half-life, rabbits and monkeys demonstrate their utility as chronic pharmacodynamic models with monthly dosing regimens. The observed half- life in rats was comparable to that observed with small molecules (in-house data) indicating the usefulness as acute models for weekly dosing. Although the drug distribution pattern is similar across species, the differences in the V/AH ratios may be attributed to differences in AH flow and/or turnover rates. Overall, the relationships established in this study can be used to simulate ocular distribution profiles in humans, while accounting for anatomical differences.
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