Wang Pilot Project Summary

The population of US adults with vision impairment and age-related eye diseases is estimated to increase substantially from 24 million in 2010 to 38 million in 2032, due to the aging population and the epidemic of chronic diseases, e.g., diabetes. Despite the preponderance of the need, the development of ophthalmic innovator drugs and generic drugs is hampered by the lack of understanding of ocular drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in terms of expression, localization, and their role in affecting ocular drug delivery and local drug exposure, as well as microsensors that are capable of measuring relevant pharmacodynamic biomarkers in ocular tissues. This knowledge gap is further exacerbated by the difficulty in measuring drug concentration in ocular tissues, which is often impractical, unethical, and/or cost prohibitive. This poses many challenges for ophthalmic drug development and regulatory assessment of new ophthalmic drugs, and in particular, generic ophthalmic drugs, because the traditional bioequivalence (BE) approach with systemic blood pharmacokinetics (PK) for orally administered drugs is usually not applicable for locally-acting ophthalmic drugs.

Here we propose to determine the ocular expression of DMEs and DTs using latest proteomic and transcriptomic approaches in Aim 1 and measure ocular PK and tissue distribution of the model ophthalmic drug latanoprost using in vivo microdialysis in Aim 2. The proposed project will be the first systematic quantification of the protein levels of ocular DMEs and DTs in rabbits, the first to evaluate drug-drug interactions at the ocular barriers, and the first to demonstrate in vivo microdialysis of optic nerve, shining new light on ocular drug disposition. These results will also provide critical preliminary data to support a new major grant application to NIH National Eye Institute (R01) or US FDA (U01) to systematically quantify ocular DMEs and DTs in humans and build an ocular physiologically-based pharmacokinetic model platform, verified by experimental microdialysis PK data, to expedite the development of new ophthalmic drugs, delivery strategies, and regulatory decision-making.

Project Title

  • Targeted proteomics and microdialysis technology platform for ocular diseases and drug development

Project Investigator