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

Abstract

The simulations with the extended model closely resemble in vivo pharmacokinetics, and the model is a valuable tool for data interpretation and predictions.

Pharmacokinetic Simulations of Intravitreal Biologicals: Aspects of Drug Delivery to the Posterior and Anterior Segments

“…Ocular pharmacokinetics can be modeled at various levels of complexity. The most complex models utilize a finite element approach that is based on accurate anatomical 3-D representation of the eye with even >30,000 compartments [19,22]. This approach allows simulation of detailed 3-D concentration gradients within the eye, but such models can be built or used only by researchers with advanced modeling skills [19].…”

“…The most complex models utilize a finite element approach that is based on accurate anatomical 3-D representation of the eye with even >30,000 compartments [19,22]. This approach allows simulation of detailed 3-D concentration gradients within the eye, but such models can be built or used only by researchers with advanced modeling skills [19]. A previous mechanistic PK/PD model for ranibizumab [8] described the drug transfer from the vitreous to the anterior chamber in the same way as we did in this study.…”

“…Our simplified model can be used for successful bottom-up simulations as the model predicted accurately the concentrations of five biologicals in the rabbit vitreous and aqueous humor after intravitreal injections. Compared to several published models of intraocular pharmacokinetics [8,10,19,22], the model presented herein (Figure 1) is simple and easily applicable with user-friendly software that utilizes a graphical user interface. The model can be widely and conveniently used in the development of ocular delivery systems for biologicals, and is particularly useful in the design of drug payload, release rate and dosing interval of drug delivery systems.…”

“…In the aqueous humor, mixing of the drug takes place rapidly, like in a mixed tank [19]. Therefore, no time delays were needed to describe drug distribution in the aqueous humor.…”

“…Transport of biologicals from the vitreous to the anterior chamber has been quantitated in many experimental rabbit studies [14,15,16,17,18]. Furthermore, this has been modeled recently with physiologically based pharmacokinetic (PBPK) and finite element models [8,19]. Since PBPK and finite element models require specialized expertise in modeling, they are not accessible to most academic and industrial investigators in the field of ocular drug delivery.…”