Simulating Intravitreal Injections in Anatomically Accurate Models for Rabbit, Monkey, and Human Eyes

Abstract

PurposeTo develop models for rabbit, monkey, and human that enable prediction of the clearance after intravitreal (IVT) injections in one species from experimental results obtained in another species.MethodsAnatomically accurate geometric models were constructed for rabbit, monkey, and human that enabled computational fluid dynamic simulation of clearance of an IVT injected bolus. Models were constructed with and without the retrozonular space of Petit. Literature data on clearance after IVT injection of substances spanning a range of molecular weight up to 157 kDa were used to validate the rabbit model.ResultsThe space of Petit had a significant increase on the clearance of slowly diffusing substances cleared by the anterior pathway by reducing the bottleneck for drug efflux. Models that did not include this zone could not accurately predict the clearance of slowly diffusing substances whose clearance was accelerated by intraocular pressure-driven convection.ConclusionsThe ocular anatomy must be carefully reconstructed in the model to enable accurate predictions of clearance. This method offers an alternative means for scaling experimental data from one species to another that may be more appropriate than other simple approaches based entirely upon scaling of compartment volumes and flow rates.

Extended Pharmacokinetic Model of the Rabbit Eye for Intravitreal and Intracameral Injections of Macromolecules: Quantitative Analysis of Anterior and Posterior Elimination Pathways

“…The local drug concentrations in different parts of the retina and choroid dictate the efficacy and safety of the drug treatment, but they cannot be modeled with traditional compartmental modeling that assumes an even drug concentration throughout the vitreous. Instead, computational fluid dynamics (CFD) based on finite element modeling (FEM) or finite volume method (FVM) must be used, because the methods employ anatomically relevant three-dimensional (3D) geometric models that consist of thousands of tiny compartments (9)(10)(11). This allows simulation of localized drug concentrations in the posterior segment of the eye.…”

“…More recently, CFD models have been built for the complete eye enabling simultaneous evaluation of drug kinetics in the anterior and posterior segments of the eye after IVT and topical application (11,(20)(21)(22)(23)(24)(25). The most comprehensive study on IVT administration was published by Missel (11) who built anatomically accurate models for human, rabbit and monkey eyes based on MRI, and validated the rabbit model using published in vivo data on six compounds with a wide range of molecular weights (0.3-157 kDa).…”

In vivo and in vitro sustained release of ranibizumab from a nanoporous thin-film device

“…While a constant rate of release is an imperfect assumption for these devices, given our estimates for the time to approach steady state we can expect the in vivo concentrations measured at weeks 4, 8 and 12 will be representative of relevant long term concentrations. Furthermore, using the average terminal release rate of 0.56 μg/d measured in vitro , reported ranibizumab clearance (t 1/2 = 2.9d), and approximate rabbit vitreous volume (V vit = 1.7ml) [36], a steady-state concentration of 1.38 μg/ml is predicted. Variations between in vitro and in vivo release rates, saturated mechanisms for clearance of ocular ranibizumab, or imperfect estimates for vitreous volumes may contribute to the deviation between the predicted steady-state concentration and the average measured vitreous concentration of 0.96 μg/ml over weeks 4, 8, and 12.…”

“…However, an increased occurrence of cataracts associated with device implantation can be attributed to the challenge of trauma-free surgical implantation in the small rabbit vitreous chamber relative to the size of the device. Because devices were designed for human treatment, the smaller vitreous cavity (1.7 ml vs 4.7–5 ml) and the larger lens (thickness 6.7 mm vs 3.89 mm) of this rabbit model compared to human anatomy are expected to contribute to an increased incidence of iatrogenic cataract formation [36,39]. …”

Induction of Ocular Complement Activation by Inflammatory Stimuli and Intraocular Inhibition of Complement Factor D in Animal Models

“…We assume that the concentration of FD in the eye should be lower than in serum (40-80 nM) 58 and rabbit vitreous volume to be around 1.52 cm 3 . 59 Intravitreal injection of 200 lg per eye would predict~0.88 lM anti-FD, which is at least 11-to 22-fold higher than FD levels in the vitreous. LPSinduced alternative pathway activation in vitreous humor as measured by Ba generation was completely blocked (Fig.…”