A Novel Eye Drop Candidate for Age-Related Macular Degeneration Treatment: Studies on its Pharmacokinetics and Distribution in Rats and Rabbits.

Eun-Jeong Choi,Hea-Young Cho,Ju Hee Kim,Go-Wun Choi,Hyun Ju Bae,Ju-Hee Lee,Yong-Bok Lee,Hee-Woon Jang,Young Gwan Kim

doi:10.3390/molecules25030663

Abstract

Age-related macular degeneration (AMD) is wearing down of macula of retina, causing a blur or loss of vision in the center of the visual field. It can be categorized into dry or wet AMD. Until now, medical treatments for dry AMD have not been developed yet. The aim of this study was to evaluate pharmacokinetics (PKs) and tissue distribution of CK41016, a novel candidate for dry AMD, after intravenous (IV) or eye drop administration in rats and rabbits. In addition, a simple and sensitive bioanalytical method for CK41016 using ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was developed. PK parameters were estimated by compartmental analysis using a WinNonlin® software version 8.1 (a Certara™ company). A PK model of CK41016 was well-described by the two-compartment model. The tissue-to-plasma partition coefficient (Kp) of CK41016 was the highest in the vitreous humor of rats and the cornea of rabbits after eye drop administration. In addition, the Caco-2 cell transporter assay confirmed that CK41016 was not an active substrate for the efflux transporter. In summary, the PKs and tissue distribution of CK41016 were successfully evaluated and investigated whether this drug was a substrate of efflux transporters.

Highlights

Age-related macular degeneration (AMD) is one of the causes of adult blindness, due to macular damage of the retina
The UPLC-MS/MS analysis in this study provided a sufficient lower limit of quantification (LLOQ) for further PK study after the intravenous and eye drop administration of CK41016 in rats and rabbits
The PK model and tissue distribution of CK41016 were successfully evaluated after IV or eye drop administrations to rats and rabbits

Summary

Introduction

Age-related macular degeneration (AMD) is one of the causes of adult blindness, due to macular damage of the retina. Symptoms of this disease include distorted vision, blurred vision, a loss in contrast sensitivity, slow recovery of visual function after exposure to bright light, and no vision in the center of the visual field [1]. AMD can be classified into wet AMD and dry AMD. About 10% of patients with AMD have wet AMD with choroidal neovascularization (CNV), which can cause vision loss. The development of laser coagulation, anti-VEGF medication, and photodynamic therapy has reduced the chances of vision loss for patients with wet AMD [2,3].

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