(584al) Tear-Dynamic-Based Pharmacokinetics Model for Ophthalmic Drug Delivery | AIChE

(584al) Tear-Dynamic-Based Pharmacokinetics Model for Ophthalmic Drug Delivery

Authors 

Peng, C. C. - Presenter, University of California, Berkeley
Radke, C., University of California-Berkeley



Despite considerable loss inefficiency (> 95 %), topical ophthalmic drug delivery remains the primary application modality to the human eye. Further, topical administration of ocular drugs is limited by uncertainty of where the drug distributes including tear drainage and spill-over loss, dilution in tear fluid, and penetration through cornea and/or conjunctiva (both bulbar and palpebral). Most studies are limited to measuring concentrations in ocular tissues over time following single or multiple administration, which prevents quantitative bioavailability predictions for changes in formulation or dosage regimen. Moreover, the majority of such studies have been conducted by animal subjects such as rabbits and rats. While the physiology properties of these ocular tissues in animal models might be representative, their tear dynamics are significantly different from that of human subjects.

In this study we present a compartmental description of tear dynamics based on human subjects that quantifies drug pharmacokinetics (PK) by topical administration including bioavailability in each compartment of the anterior eye. The tear supply/drainage system is divided into 5 compartments: upper and lower menisci, upper and lower conjunctival sacs, and tear film.1 A transient description is employed for each compartment for tear volume, salinity, and drug concentration. Compartments are coupled to each other and to drug delivery through kinetic routes.

This tear-dynamic-based PK model was first examined by predicting drug distribution for topical dosing of timolol by eye drop. The results indicate a residence time of drug in precorneal tear film of about 6 min; ocular bioavailability to cornea is about 5% for normal subjects. Furthermore, our model allows us to predict the effect of drop size and dosing sequences on the drug loss to conjunctiva and tear drainage, which is directly related to the systemic side effect of drug delivery. Current delivery models make no distinction on where the drug resides. Another case study predicts precorneal residence time of a fluorescent tracer mixed with commercial artificial tears. The viscosity of solution depends on the concentration of active agent (biocompatible polymers). Although dilution reduces the initial high viscosity, thickness (volume) of precorneal tear film increases and tear drainage rate decrease, thus extending drug residence time. These predictions are consistent with clinical observations.2

The proposed tear-dynamics model is the first attempt to develop a topical ocular drug-delivery model based on compartmental tear dynamics. The model is especially useful for optimizing drug formulations and dose regimens for both normal and dry-eye subjects and, thus, for streamlining FDA approval. Further, quantitative prediction of conjunctival uptake can be integrated with available PK models to improve drug uptake prediction accuracy in both the anterior and posterior segments of eye. The new model is suitable for quantifying ocular drug delivery by other vehicles including contact lens, and emulsion and nanoparticle suspensions.

1. Cerretani C, Radke CJ. Current Eye Research 2013; submitted

2. Paugh JR, Nauyen AL, Ketelson HA, Christensen MT, Meadows DL. Optom Vis Sci. 2008;85:725-731.