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

Abstract

Tyrosine kinase inhibitors (TKIs) are an example of targeted drug therapy to treat cancer while minimizing damage to healthy tissue. In contrast to traditional oncology drugs, the toxicity profile of targeted therapies is less well understood and can include severe ocular adverse events, which are among the most common toxicity reported by these therapeutics. Inhibition of Mer receptor tyrosine kinase (MERTK) promotes innate tumor immunity by decreasing M2-macrophage polarization and efferocytosis. This mechanism offers the opportunity for targeted immunotherapy to treat cancer; however, the ocular expression of MERTK increases the difficulty for developing a targeted drug due to toxicity concerns. In this article we review the pharmacokinetic (PK) parameters and in vitro absorption, distribution, metabolism, and excretion (ADME) assays available to evaluate ocular disposition and assess the relationship between clinical PK and reported ocular events for TKIs to allow backtranslation to preclinical models. Understanding the ocular disposition in the context of PK and safety remains an evolving area and is likely to be a key aspect of developing safe and efficacious oncology drugs, devoid of ocular toxicity.