Novel Endogenous Glycan Therapy for Retinal Diseases: Safety,In Vitro Stability,Ocular Pharmacokinetic Modeling,and Biodistribution |
| |
Authors: | Shankar Swaminathan Huiling Li Mallika Palamoor Walter T Luchsinger de Obarrio Dorababu Madhura Bernd Meibohm Monica M Jablonski |
| |
Institution: | 1. Department of Ophthalmology, Hamilton Eye Institute, The University of Tennessee Health Science Center, 930 Madison Avenue, Suite 731, Memphis, Tennessee, 38163, USA 2. Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USA
|
| |
Abstract: | Asialo, tri-antennary oligosaccharide (NA3 glycan) is an endogenous compound, which supports proper folding of outer segment membranes, promotes normal ultrastructure, and maintains protein expression patterns of photoreceptors and Müller cells in the absence of retinal pigment epithelium support. It is a potential new therapeutic for atrophic age-related macular degeneration (AMD) and other retinal degenerative disorders. Herein, we evaluate the safety, in vitro stability, ocular pharmacokinetics and biodistribution of NA3. NA3 was injected into the vitreous of New Zealand white rabbits at two concentrations viz. 1 nM (minimum effective concentration (MEC)) and 100 nM (100XMEC) at three time points. Safety was evaluated using routine clinical and laboratory tests. Ocular pharmacokinetics and biodistribution of 3H]NA3 were estimated using scintillation counting in various parts of the eye, multiple peripheral organs, and plasma. Pharmacokinetic parameters were estimated by non-compartmental modeling. A 2-aminobenzamide labeling and hydrophilic interaction liquid interaction chromatography were used to assess plasma and vitreous stability. NA3 was well tolerated by the eye. The concentration of NA3 in eye tissues was in the order: vitreous?>?retina?>?sclera/choroid?>?aqueous humor?>?cornea?>?lens. Area under the curve (0 to infinity) (AUC∞) was the highest in the vitreous thereby providing a positive concentration gradient for NA3 to reach the retina. Half-lives in critical eye tissues ranged between 40 and 60 h. NA3 concentrations were negligible in peripheral organs. Radioactivity from 3H]NA3 was excreted via urine and feces. NA3 was stable at 37°C in vitreous over a minimum of 6 days, while it degraded rapidly in plasma. Collectively, these results document that NA3 shows a good safety profile and favorable ocular pharmacokinetics.Electronic supplementary materialThe online version of this article (doi:10.1208/s12248-014-9563-1) contains supplementary material, which is available to authorized users.Key words: age-related macular degeneration (AMD), NA3 glycan, pharmacokinetics, safety |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|