Ocular Pharmacokinetics and Tissue Distribution of INO-8875, an Adenosine A1 Agonist, in Preclinical Species by Quantitative Whole Body Autoradiography (QWBA) and Liquid Chromatography/Tandem Mass Spectrometry (LC/MS/MS)

Abstract

Purpose: : INO-8875, a selective adenosine A₁ receptor agonist, is under development for treatment of ocular hypertension and primary open-angle glaucoma (POAG). INO-8875 lowers intraocular pressure (IOP) by increasing conventional outflow facility via the trabecular meshwork (TM). The purpose of this work was to assess the pharmacokinetics (PK) and ocular and systemic tissue distribution of INO-8875 following topical ocular administration to animals.

Methods: : INO-8875 was evaluated in normotensive rabbits, dogs and monkeys after topical ocular administration. Ocular and systemic PK, tissue distribution and mass balance were studied using both radiolabeled and unlabeled INO-8875. Bioanalysis was accomplished using LC/MS/MS for unlabeled drug and liquid scintillation counting or QWBA for ¹⁴C-INO-8875.

Results: : Following topical ocular administration of INO-8875, ocular drug levels in key target tissues in the anterior globe (cornea, aqueous humor, TM and ciliary body) were highly concentrated for up to 6 hr, and typically one to two orders of magnitude higher than in plasma up to 48 hr post-dose. Following ocular administration of ¹⁴C-INO-8875, radioactivity was distributed into ocular and systemic tissues at 0.25 hr post-dose, with greatest ocular exposure in the anterior globe, in particular cornea, without melanin binding. Nasolacrimal drainage was significant while ¹⁴C-INO-8875-related material did not penetrate the blood:brain barrier. High levels of radioactivity in kidney and liver suggest both hepatic and renal clearance. Systemic exposure to INO-8875 after ocular administration was low overall, with a short plasma half-life (<0.7 hr) across species.

Conclusions: : INO-8875, a selective adenosine A₁ agonist, rapidly accesses the site of action after topical ocular instillation. Long-lasting drug concentrations in ocular target tissues with low systemic exposure and rapid clearance result in favorable safety and pharmacodynamic profiles for INO-8875.

Keywords: adenosine • intraocular pressure • trabecular meshwork