Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route

Abstract

The eye is a complex organ with a series of anatomic barriers that provide protection from physical and chemical injury while maintaining homeostasis and function. The physiology of the eye is multifaceted, with dynamic flows and clearance mechanisms. This review highlights that in vitro ocular transport and metabolism models are confined by the availability of clinically relevant absorption, distribution, metabolism, and excretion (ADME) data. In vitro ocular transport models used for pharmacology and toxicity poorly predict ocular exposure. Although ocular cell lines cannot replicate in vivo conditions, these models can help rank-order new chemical entities in discovery. Historic ocular metabolism of small molecules was assumed to be inconsequential or assessed using authentic standards. While various in vitro models have been cited, no single system is perfect, and many must be used in combination. Several studies document the use of laboratory animals for the prediction of ocular pharmacokinetics in humans. This review focuses on the use of human-relevant and human-derived models which can be utilized in discovery and development to understand ocular disposition of new chemical entities. The benefits and caveats of each model are discussed. Furthermore, ADME case studies are summarized retrospectively and capture the ADME data collected for health authorities in the absence of definitive guidelines. Finally, we discuss the novel technologies and a hypothesis-driven ocular drug classification system to provide a holistic perspective on the ADME properties of drugs administered by the ocular route.

In vitro reconstructed 3D corneal tissue models for ocular toxicology and ophthalmic drug development

“…In addition, due to the differences in anatomy and morphology of the eyes, they do not accurately mimic the human cornea (Agarwal and Rupenthal 2016). Research efforts have been directed toward developing 3D corneal models and more realistic equivalents to study wound healing, drug permeation, and availability (Toropainen et al 2001;Elliott and Yuan 2011;Dumouchel et al 2018;Kaluzhny et al 2018), as well as ocular toxicity (Curren and Harbell 2002;Elliott and Yuan 2011;Shafaie et al 2016). In contrast to in vivo and ex vivo models, in vitro cell-based models offer the advantage of being simple, less time consuming, and reproducible, while providing a mechanistic understanding of the results on the cellular and molecular level (Wilson et al 2015;Lotz et al 2016).…”

“…In this view, many tumor or immortalized cell lines are not suitable to replace animal models since they lack these in vivo characteristics. Others argue that a single in vitro reconstructed corneal tissue model, no matter how complex, will not be able to correctly predict human toxicity and completely replace animal studies (Abdelkader et al 2015;Dumouchel et al 2018). This approach reasons that more specialized in vitro tissue models can be used to address specific toxicological mechanisms in a stepwise (tiered) approach with the ultimate goal of entirely replacing animal studies to predict human effects (Curren and Harbell 2002;.…”

Blood retinal barrier and ocular pharmacokinetics: Considerations for the development of oncology drugs

“…Extraction of each ocular tissue is not possible and these assays rely on homogenization of the whole eye. However, homogenization of the whole eye may dilute the metabolic enzymes and misrepresent the metabolism at the individual tissue (Dumouchel et al., 2018).…”

“…While the lens will have no direct impact on PK, it will influence the volume of other ocular compartments that have been shown to impact PK, for example, the vitreous volume. The volume of the vitreous and subsequent compound elimination from this ocular compartment is often used to interpret ocular PK and define safety margins for systemically administered compounds (Del Amo et al., 2017; Vellonen et al., 2016), however, significant caution has been noted for the vitreous volumes noted in the literature (Dumouchel et al., 2018; Vellonen et al., 2016). The blood aqueous barrier may also contribute to the permeability of drugs out of the eye; however, the literature is often contradictory, making it difficult to define the impact on PK (Del Amo et al., 2017; Liu & Liu, 2019; Tournier et al., 2018).…”

Emerging Models of Drug Metabolism, Transporters, and Toxicity

“…In addition to permeability assessments, understanding the disposition, distribution, and toxicology of molecules across the corneal epithelium is of importance. In this issue, Dumouchel et al (2018) reviewed additional in vitro ocular models derived from primary systems to study the disposition and toxicity of small molecules. This mini-review discusses the advantages and disadvantages of ocular cell lines, ocular tissue homogenates and tissue sections, and ocular subcellular fractions, with the caveat that extensive pharmacokinetic data on human ocular disposition are not available.…”