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Muhammad Abdulrazik; Novel modeling for the Enhancement of Decision-Making Worthiness of Ocular Pharmacokinetic Study Results. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4005.
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© ARVO (1962-2015); The Authors (2016-present)
Enhancing the credibility of decisions based on ocular pharmacokinetic (PK) study results.
In two PK studies a single dose, of brimonidine tartrate (0.2%) or dexamethasone base (0.1 %), was instilled in the cul-de-sac of one eye of an albino rabbit. The whole-tissue-weight (WTW [gr]) was measured and drug concentrations were determined (at 15, 30 and 60 min. post instillation) for each of conjunctiva, cornea, sclera, ciliary-body, iris, choroid, aqueous-humor, lens, vitreous and retina. Fraction-of-administered-dose (FOAD [%]) was calculated from the administered dose (AD [ng]), drug concentration (C [ng/gr]) and WTW (FOAD=100.C.WTW/AD). Area-under-the-curve (AUC, 0-60 min. [ng.min/gr]) for each tissue is presented as % of the sum of AUC's for all tissues. Cubes-under-the-curve (CUC [ng.min]) is introduced as a per-whole-tissue PK parameter (CUC=AUC.WTW), in contrast to the per-gram AUC.
Brimonidine retention in all ten tissues scored only 3.8±1.02% FOAD. The conjunctival stake, out of this, was 65.74±4.52% (FOAD), 66.18±2.68% (CUC) and 37.84±4.03% (AUC). Inside the non-conjunctival tissues stake: cornea and sclera, 42.81±7.59% (FOAD), 40.30±6.51% (CUC) and 42.79±2.97% (AUC); uveal tract tissues, 34.27±3.91% (FOAD), 35.68±3.18% (CUC) and 44.13±1.56% (AUC); aqueous humor, 11.16±3.89% (FOAD), 12.53±3.24% (CUC) and 7.7±1.61% (AUC); lens and vitreous, 8.63±0.75% (FOAD), 8.47±0.17% (CUC) and 1.63±0.11% (AUC); retina, 3.13±0.46% (FOAD), 3.03±0.11% (CUC) and 3.75±0.21% (AUC). In dexamethasone treated eye, the ten tissues, altogether, scored 4.04±0.56% FOAD. The conjunctival stake, out of this, was 67.85±2.41% (FOAD), 67.71±1.49% (CUC) and 37.34±1.16% (AUC). Inside non-conjunctival tissues stake: cornea and sclera, 62.05±8.37% (FOAD), 65.02±7.04% (CUC) and 69.25±5.78% (AUC); uveal tract tissues, 21.43±5.76% (FOAD), 19.41±4.84% (CUC) and 21.99±5.11% (AUC); aqueous humor, 6.63±1.65% (FOAD), 6.04±1.28% (CUC) and 3.42±0.66% (AUC); lens and vitreous, 6.01±1.09% (FOAD), 5.62±0.91% (CUC) and 0.90±0.07% (AUC); retina, 3.89±0.23% (FOAD), 3.91±0.07% (CUC) and 4.44±0.07% (AUC).
Ocular tissues are at diverse range of WTW. The AUC, inherently, underestimates drug retention at tissues with relatively high WTW, like the conjunctiva. Both FOAD and CUC, being WTW based, promise a significant enhancement to the credibility of decisions based on ocular pharmacokinetic study results.
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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