No abstract

Purpose Many clinical drugs bind to melanin pigment in ocular tissues, affecting their pharmacokinetics in the eye. Drug‐melanin binding is frequently studied in vitro with isolated or synthetic melanin. The effect of other factors, such as permeability of melanosomal and plasma membrane, dissociation rate from melanin, melanin content of the tissue and ion trapping in melanosomes, are poorly understood. This study aims to probe the impact of the above‐mentioned factors together with melanin binding on drug retention in the pigmented retinal pigment epithelium (RPE) and choroid by kinetic simulations. Methods We simulated drug retention in the RPE‐choroid after intravitreal and systemic administration of a high and a moderate melanin‐binding drug using a bottom‐up approach with Stella software. The model parameters were based on realistic values from experimental studies and the model integrated these parameters together allowing the exploration of their interplay. Results The high melanin binder was retained in the pigmented but not in the non‐pigmented RPE‐choroid after both intravitreal and systemic administration. Lowering the cell membrane permeability increased retention, but changes in dissociation rate from melanin had minimal effect. Ion trapping in melanosomes increased retention. The moderate melanin binder was not retained considerably in the pigmented RPE‐choroid, although the concentrations increased compared to the non‐pigmented RPE‐choroid. Lowering the permeability values and dissociation rate lengthened the retention in the pigmented RPE‐choroid. Conclusions Melanin binding can accumulate high‐binding drugs into pigmented tissues, but other factors, including melanosomal and plasma membrane permeability, ion trapping in melanosomes, and dissociation rate from melanin, play an important role in drug distribution to pigmented ocular tissues.

Summary Ocular pharmacokinetics is of crucial importance in ocular drug delivery and pharmacodynamics. Posterior segment drug pharmacokinetics is particularly important, since it seriously limits the applicable routes of drug delivery in the retinal treatment. In this presentation, some important aspects of posterior segment pharmacokinetics will be discussed, such as the role of blood retina barrier, drug transporters, and melanin binding. Quantitative and systematic pharmacokinetics approaches will be presented and discussed in the light of pharmacodynamics and drug delivery.