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D. F. Welty, J.-E. Lin, M. Attar, A. Acheampong, M. R. Robinson, S. M. Whitcup, B. D. Kuppermann; Pharmacokinetics and Pharmacodynamics of the Sustained-Release Dexamethasone Intravitreal Implant. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3797.
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To determine the pharmacokinetics and pharmacodynamics of the sustained-release dexamethasone (DEX) intravitreal implant (Ozurdex; Allergan, Inc.).
Male cynomolgus monkeys (N = 34) received bilateral 700-µg DEX intravitreal implants. Blood, vitreous humor, and retina samples were collected at predetermined intervals up to 271 days after administration. Dexamethasone was quantitated by liquid chromatography-tandem mass spectrometry and cytochrome P450 3A8 (CYP3A8) gene expression was analyzed by real-time reverse transcriptase polymerase chain reaction.
High concentrations of DEX were detected in vitreous humor and retina samples during the first 2 months followed by low concentrations from 3 to 6 months. After 6 months, DEX was below the limit of quantitation. The Cmax (Tmax) and AUC for the vitreous humor were 213 ng/mL (Day 61) and 11,300 ng·days/mL, respectively, and for the retina were 1110 ng/g (Day 61) and 47,200 ng·days/g, respectively. The Cmax (Tmax) of DEX in plasma was 1.11 ng/mL (Day 61). Compared with control eyes that did not receive the DEX intravitreal implant, CYP3A8 expression in the retina was upregulated 3 -fold up to 6 months post-administration of the implant (0.969 ± 0.057 vs 3.07 ± 0.438; P < 0.05 up to 2 month samples).
The in vivo release profile of the DEX intravitreal implant in monkey eyes is characterized by high drug concentrations observed early, followed by a prolonged period of low concentrations, which is similar to previous PK research of pulse dosing with systemic corticosteroids.These results are consistent with clinical studies supporting the use of the DEX intravitreal implant for the extended management of posterior segment diseases.
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