Intravitreal administration of known phototoxicants in the rabbit fails to produce phototoxicity: implications for phototoxicity testing of intravitreally administered small molecule therapeutics
Abstract:These data suggest that the posterior segment of the rabbit eye is protected against phototoxicity by anatomical and/or physiological mechanisms, and is not a useful model for the assessment of phototoxicity of intravitreally administered molecules.
“…Specifically, we wished to compare ex vivo results using GNE-947 to those using Triesence (triamcinolone acetonide) as a control. Triesence is a marketed ITV suspension with similar formulation components to GNE-947 that has not been observed to migrate anteriorly [ 11 ]. Figure 4 Adverse anterior drug particle movements are recapitulated in perfused NHP and human eyes.…”
Section: Resultsmentioning
confidence: 99%
“…However, as new treatments are developed, a major translational challenge has arisen; predicting and optimizing the disposition of ITV drugs and their excipients for the human eye [ 8 , 9 ]. One prominent, but poorly understood issue often observed in pre-clinical toxicology studies has been the anterior movement of drug or excipient particles from the vitreal compartment to the anterior chamber (AC) [ 10 , 11 ]. These outcomes are consistent with clinical observations of migrating pigment or retinal debris in the same direction [ 12 – 14 ].…”
Intravitreal (ITV) drug delivery is a new cornerstone for retinal therapeutics. Yet, predicting the disposition of formulations in the human eye remains a major translational hurdle. A prominent, but poorly understood, issue in pre-clinical ITV toxicity studies is unintended particle movements to the anterior chamber (AC). These particles can accumulate in the AC to dangerously raise intraocular pressure. Yet, anatomical differences, and the inability to obtain equivalent human data, make investigating this issue extremely challenging. We have developed an organotypic perfusion strategy to re-establish intraocular fluid flow, while maintaining homeostatic pressure and pH. Here, we used this approach with suitably sized microbeads to profile anterior and posterior ITV particle movements in live versus perfused porcine eyes, and in human donor eyes. Small-molecule suspensions were then tested with the system after exhibiting differing behaviours
in vivo
. Aggregate particle size is supported as an important determinant of particle movements in the human eye, and we note these data are consistent with a poroelastic model of bidirectional vitreous transport. Together, this approach uses ocular fluid dynamics to permit, to our knowledge, the first direct comparisons between particle behaviours from human ITV injections and animal models, with potential to speed pre-clinical development of retinal therapeutics.
“…Specifically, we wished to compare ex vivo results using GNE-947 to those using Triesence (triamcinolone acetonide) as a control. Triesence is a marketed ITV suspension with similar formulation components to GNE-947 that has not been observed to migrate anteriorly [ 11 ]. Figure 4 Adverse anterior drug particle movements are recapitulated in perfused NHP and human eyes.…”
Section: Resultsmentioning
confidence: 99%
“…However, as new treatments are developed, a major translational challenge has arisen; predicting and optimizing the disposition of ITV drugs and their excipients for the human eye [ 8 , 9 ]. One prominent, but poorly understood issue often observed in pre-clinical toxicology studies has been the anterior movement of drug or excipient particles from the vitreal compartment to the anterior chamber (AC) [ 10 , 11 ]. These outcomes are consistent with clinical observations of migrating pigment or retinal debris in the same direction [ 12 – 14 ].…”
Intravitreal (ITV) drug delivery is a new cornerstone for retinal therapeutics. Yet, predicting the disposition of formulations in the human eye remains a major translational hurdle. A prominent, but poorly understood, issue in pre-clinical ITV toxicity studies is unintended particle movements to the anterior chamber (AC). These particles can accumulate in the AC to dangerously raise intraocular pressure. Yet, anatomical differences, and the inability to obtain equivalent human data, make investigating this issue extremely challenging. We have developed an organotypic perfusion strategy to re-establish intraocular fluid flow, while maintaining homeostatic pressure and pH. Here, we used this approach with suitably sized microbeads to profile anterior and posterior ITV particle movements in live versus perfused porcine eyes, and in human donor eyes. Small-molecule suspensions were then tested with the system after exhibiting differing behaviours
in vivo
. Aggregate particle size is supported as an important determinant of particle movements in the human eye, and we note these data are consistent with a poroelastic model of bidirectional vitreous transport. Together, this approach uses ocular fluid dynamics to permit, to our knowledge, the first direct comparisons between particle behaviours from human ITV injections and animal models, with potential to speed pre-clinical development of retinal therapeutics.
“…Phototoxicity testing for small molecules should be based on patient demographics, pharmacological class, and health authority input. If needed, the 3 T3 in vitro assay and a phototoxicity study in rat may be considered (because IVT administration of known phototoxicants do not produce ocular phototoxicity in Dutch‐Belted rabbits) 73 …”
The eye, which is under constant exposure to environmental pathogens, has evolved various anatomic and immunological barriers critical to the protection of tissues lacking regenerative capacity, and the maintenance of a clear optic pathway essential to vision. By bypassing the ocular barriers, intravitreal (IVT) injection has become the mainstay for the delivery of drugs to treat conditions that affect the back of the eye. Both small molecules and biotherapeutics have been successfully administered intravitreally, and several drugs have been approved for the treatment of (wet) age-related macular degeneration and diabetic macular edema. However, IVT injection is an invasive procedure, which requires sufficient technical expertise from the healthcare professional administering the drug.Potential side effects include bleeding, retinal tear, cataracts, infection, uveitis, loss of vision, and increased ocular pressure. Pharmaceutical companies often F I G U R E 1 Structures and compartments of the eye. 19 Hematoxylin-eosin-stained section of a whole dog eye. The anterior segment is divided into the anterior and posterior chambers, which are anatomically delineated by the AH; cornea, sclera, and conjunctiva; ICA; the ciliary processes, and iris body. Behind the lens, the posterior segment includes the VB; retina and ora serrata; the choroid and sclera; and the optic nerve.
“…Ello se satisface particularmente en dos situaciones: el registro de ondas coda de eventos sísmicos de magnitud considerable (Campillo and Paul, 2003), o bien, en el caso de perturbaciones de energía relativamente menor en un medio de baja disipación anelástica (Hennino et al, 2001). En el caso de fuentes de ruido, la suposición de un campo de ondas difuso ha conducido a una paradoja: si bien en la práctica su utilidad es incuestionable (Lobkis and Weaver, 2003;Wapenaar, 2004;Roux et al, 2005;Sánchez-Sesma and Campillo, 2006;Snieder, 2007), la presencia de campos difusos resulta realmente improbable (Mulargia, 2012) producto de la distribución heterogénea de las fuentes de ruido. Ello se soluciona comprobando que una caracterización eficaz del subsuelo es aún posible en presencia de un amplio espectro de campos de ondas, con condiciones más flexibles que la difusividad del campo (Mulargia and Castellaro, 2008).…”
Section: Iv4 Campos Difusos Y Ruido Sísmico Ambientalunclassified
Quiero agradecer, en primer lugar, a los directores de esta tesis doctoral, Gabriela y Deyan. Agradezco a ambos por brindar las condicionesóptimas para mi desarrollo personal como joven científico, valorando mi trabajo, confiando en mis ideas, aportando en todo momento las suyas, motivándome con sus ganas de progresar e innovar, y haciéndome partícipe de sus tareas.Quiero agradecer a las personas que han brindado, en mayor o menor medida, tiempo y conocimiento para que cada una de las metodologías implementadas en esta tesis haya podido ser realizada de la mejor manera posible;
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