Ocular pharmacokinetics of a novel class of corticosteroids with ROCK inhibitory activity and potential for reduced steroid-associated risks

Abstract

Purpose : The anti-inflammatory efficacy of corticosteroids in ocular inflammatory conditions is well-established. However, risks of long-term steroid use include steroid-induced ocular glaucoma, which is thought to develop as extracellular matrix proteins accumulate and impair proper function of the trabecular meshwork (TM). Rho kinase inhibition (ROCKi) has been shown to attenuate steroid-induced collagen and fibronectin deposition in cultured TM cells. Furthermore, ROCKi has been shown to lower IOP by increasing aqueous outflow through the TM. Inhibition of ROCK during steroid use for ocular inflammatory conditions may provide a strategy to decrease the risk for steroid-induced glaucoma. Here we demonstrate the in-vitro stability and corneal metabolism of a new class of corticosteroids with ROCKi activity. We also show the ocular tissue distribution of lead candidates, and their metabolites, following topical instillation.

Methods : Multiple compounds were synthesized to contain a steroid covalently linked to the active metabolite of netarsudil, AR-13503. The in vitro stability and ex vivo corneal metabolism of the compounds were determined. Ocular tissue distribution in mice was measured post-tissue harvest by HPLC-mass spectrometry following topical administration of these compounds.

Results : Lead compounds demonstrated good stability profiles in vitro. The corticosteroid and ROCKi metabolites were detected in corneal explants. Following topical dosing with the ROCK-steroids, physiologically relevant levels of both corticosteroid and the ROCKi were found in the cornea, conjunctiva, and meibomian glands of mice.

Conclusions : We have developed a novel corticosteroid with inhibitory activity against ROCK and, thus, strong potential to reduce risks associated with conventional corticosteroids. Our data demonstrate the favorable pharmacokinetic profile of ROCK-steroid compounds for topical anti-inflammatory applications.

This is a 2021 ARVO Annual Meeting abstract.