Drug and Gene Delivery to the Back of the Eye: From Bench to Bedside

Rowe-Rendleman, Cheryl L.; Durazo, Shelley A.; Kompella, Uday B.; Rittenhouse, Kay D.; Polo, Adriana Di; Weiner, Alan M.; Grossniklaus, Hans E.; Naash, Muna I.; Lewin, Alfred S.; Horsager, Alan; Edelhauser, Henry F.

doi:10.1167/iovs.13-13707

Cited by 100 publications

(79 citation statements)

References 72 publications

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“…Therefore, ocular pharmacokinetics relies on animal models, mostly rabbits. Recently, the rabbit eye has been criticized for being a poor model of the human eye (Laude et al, 2010;Rowe-Rendleman et al, 2014). Therefore, we investigated all available intravitreal pharmacokinetic data in rabbits (del Amo et al, 2015) and humans (this review) and derived the pharmacokinetic parameters (clearance, volume of distribution) to compare systematically intravitreal pharmacokinetics in man and rabbit.…”

Section: Introductionmentioning

confidence: 99%

Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data

Amo

Urtti

2015

Experimental Eye Research

182

136

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Intravitreal administration is the method of choice in drug delivery to the retina and/or choroid. Rabbit is the most commonly used animal species in intravitreal pharmacokinetics, but it has been criticized as being a poor model of human eye. The critique is based on some anatomical differences, properties of the vitreous humor, and observed differences in drug concentrations in the anterior chamber after intravitreal injections. We have systematically analyzed all published information on intravitreal pharmacokinetics in the rabbit and human eye. The analysis revealed major problems in the design of the pharmacokinetic studies. In this review we provide advice for study design. Overall, the pharmacokinetic parameters (clearance, volume of distribution, half-life) in the human and rabbit eye have good correlation and comparable absolute values. Therefore, reliable rabbit-to-man translation of intravitreal pharmacokinetics should be feasible. The relevant anatomical and physiological parameters in rabbit and man show only small differences. Furthermore, the claimed discrepancy between drug concentrations in the human and rabbit aqueous humor is not supported by the data analysis. Based on the available and properly conducted pharmacokinetic studies, the differences in the vitreous structure in rabbits and human patients do not lead to significant pharmacokinetic differences. This review is the first step towards inter-species translation of intravitreal pharmacokinetics. More information is still needed to dissect the roles of drug delivery systems, disease states, age and ocular manipulation on the intravitreal pharmacokinetics in rabbit and man. Anyway, the published data and the derived pharmacokinetic parameters indicate that the rabbit is a useful animal model in intravitreal pharmacokinetics.

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Section: Introductionmentioning

confidence: 99%

Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data

Amo

Urtti

2015

Experimental Eye Research

182

136

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“…Intravitreal injections have been considered the preferred route of drug delivery to the eye during the past 2 decades, and they are the most effective drug delivery method for the retina. [4][5][6][7] Compared with systemic administration, this method has the advantages of localizing the drug effect with higher drug concentrations in the vitreous and retina. It is commonly performed by injecting a drug suspension or solution into the vitreous cavity in the center of the eye via pars plana using a 30 G needle.…”

Section: Introductionmentioning

confidence: 99%

Visual tracing of diffusion and biodistribution for amphiphilic cationic nanoparticles using photoacoustic imaging after ex vivo intravitreal injections

Xu¹,

Xu²,

Liu³

et al. 2016

IJN

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To visually trace the diffusion and biodistribution of amphiphilic cation micelles after vitreous injection, various triblock copolymers of monomethoxy poly(ethylene glycol)–poly(ε-caprolactone)–polyethylenimine were synthesized with different structures of hydrophilic and hydrophobic segments, followed by labeling with near-infrared fluorescent dye Cyanine5 or Cyanine7. The micellar size, polydispersity index, and surface charge were measured by dynamic light scattering. The diffusion was monitored using photoacoustic imaging in real time after intravitreal injections. Moreover, the labeled nanoparticle distribution in the posterior segment of the eye was imaged histologically by confocal microscopy. The results showed that the hydrophilic segment increased vitreous diffusion, while a positive charge on the particle surface hindered diffusion. In addition, the particles diffused through the retinal layers and were enriched in the retinal pigment epithelial layer. This work tried to study the diffusion rate via a simple method by using visible images, and then provided basic data for the development of intraocular drug carriers.

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“…There are solid or hollow microneedles available, which were initially developed for transdermal application. Microneedles can deliver free or encapsulated drugs with minimal invasion and may avoid the safety concerns associated with repeated intravitreal applications (Rowe-Rendleman et al 2014). Based on animal studies, it was reported that insertion site disappears 1 h after microneedle injection .…”

Section: Microneedlesmentioning

confidence: 99%