Ocular Pharmacokinetics of Intravitreally Administered Brimonidine and Dexamethasone in Animal Models With and Without Blood–Retinal Barrier Breakdown

Abstract

In animal models with a breakdown of the blood-retina barrier, drug clearance could be increased, resulting in lower drug concentration in ocular tissues compared to normal animals. However, the extent of difference may be compound- and disease model-specific. Therefore, extrapolation of ocular pharmacokinetic data obtained in normal animals to disease models for the purpose of pharmacokinetic/pharmacodynamic data analysis should be performed with caution.

A comprehensive insight on ocular pharmacokinetics

“…Also a higher intravitreal clearance was observed in diseased animals. These results suggested that PK/PD outcome depends on various factors such as drug properties as well as normal or disease model (59). Therefore, appropriate design and selection of animal model to investigate ocular PK/PD is pivotal.…”

“…It is necessary to study the pharmacokinetics profile of anti-glaucoma drugs in animal models to determine efficacy in the treatment of glaucoma in patients eventually. Pharmacokinetics parameters of these drugs are different in normal and diseased ocular tissues as illustrated in table 4 (59). In the study performed by Shen et al, (59) it was observed that AUC and C max for both the drugs were significantly lower in the disease model compared to normal animals.…”

“…Pharmacokinetics parameters of these drugs are different in normal and diseased ocular tissues as illustrated in table 4 (59). In the study performed by Shen et al, (59) it was observed that AUC and C max for both the drugs were significantly lower in the disease model compared to normal animals. This is to be expected as BRB breaks down; there is a decreased exposure of drugs to diseased ocular tissues.…”

Pharmacological and pharmacokinetic profile of the novel ocular hypotensive prodrug CKLP1 in Dutch-belted pigmented rabbits

“…For rabbits injected with CKLP1 intravenously, central ear vein blood was collected at 5 min, 15 min, 30 min, 60 min, 2h, 4h, 8h and 24h following dosing (day 1). For the first 4 time points (5,15, 30 and 60 min), animals were anesthetized with 75 mg/kg ketamine, 5mg/kg xylazine and 1 mg/kg acepromazine injected intramuscularly. Following the 60 min time point, rabbits were given 120 ml of plasmalyte subcutaneously to rehydrate.…”

“…Both CKLP1 and levcromakalim are eliminated from the plasma with relatively short terminal half-lives. Dutch-belted pigmented rabbits have been used to perform pharmacokinetic studies for several FDA-approved glaucoma medications [15,16]. The Dutch-belted rabbit is a suitable species for evaluating ocular and systemic tissue distribution, and this model can also provide quantitative ocular and plasma pharmacokinetic data.…”