Subclinical Increased Anterior Stromal Reflectivity With Topical Taprenepag Isopropyl

Taprenepag isopropyl (PF-04217329) is a highly selective EP2 receptor agonist that reduces intraocular pressure (IOP) in animals and humans.1-3 In a 2-stage, phase 2 clinical trial of taprenepag, 28 days of monotherapy reduced IOP by approximately 6.5 mm Hg, comparable with 0.005% latanoprost in ocular hypertensive and open-angle glaucoma subjects.1 However, this positive efficacy was accompanied by treatment-related adverse events of conjunctival hyperemia, photophobia, and an increase in corneal thickness of mild to moderate severity within 7 days of dosing. The increased corneal thickness did not seem to be related to the dose of taprenepag or whether it was monotherapy or combination therapy. The cornea returned to its baseline thickness within approximately 1 month of discontinuing the medication.1 The formulation of taprenepag in these studies contained benzalkonium chloride, which has been shown to increase corneal thickness4; however, taprenepag vehicle and 0.005% latanoprost controls contained equivalent concentrations of benzalkonium chloride and did not induce significant changes in corneal thickness.1 In addition, these formulations of taprenepag did not induce increased corneal thickness in rabbits or dogs.2 Only at doses approximately 10 times the taprenepag dose tested clinically was an increase in corneal thickness observed in monkeys.3 This increase in corneal thickness in monkeys resolved within 2 weeks after discontinuation of taprenepag. Neither in vivo specular microscopy nor in vitro histological or transmission electron microscopic examination of the corneas of the monkeys that were killed revealed any taprenepag toxicity to the cornea or its endothelium.3 Confocal microscopy has emerged as an invaluable tool in the evaluation and diagnosis of many ocular surface disorders because it allows for a noninvasive, high-magnification evaluation of the corneal layers. Due to its ability to produce images in vivo at a microstructural level, it is increasingly used in both laboratory and clinical settings. Multiple in vivo animal and human studies have demonstrated that confocal microscopy is a reliable and effective method for detecting microscopic corneal abnormalities of the ocular surface.5-8 However, this technology has had limited use for the assessment of a topical medication on other layers of the cornea. The purpose of this study was to determine the etiology of taprenepag-related increase in corneal thickness with standard clinical testing along with analysis of in vivo confocal microscopic scan of the entire cornea. In particular, the measurement of changes in stromal reflectivity, as an indirect indicator of changes in corneal hydration, was explored to detect possibly subtle changes in this parameter that could provide an insight into the change in corneal thickness not clinically notable. The plan was to assess quantitatively and qualitatively confocal images of the corneal epithelium, midstromal keratocytes, and endothelium. In addition, the average light intensity reflected from the anterior stroma and midstroma was compared to determine whether the increased corneal thickness was due to a disturbance of the corneal epithelium or endothelium affecting this light intensity. If the epithelium was the origin, the anterior stroma should be excessively hydrated and scatter more light than the midstroma. If the endothelium was the origin, then the reverse should be true. By measuring the average light intensity, reflectivity, of the anterior stromal and midstromal images, the etiology of the increase in corneal thickness, and therefore hydration, should be suggested. Assessment of stromal reflectivity is more sensitive to subtle changes in corneal hydration than reflectivity of the superficial and/or basal corneal epithelium because of the normal increased light scattering from these layers and the potential confounding effect of cellular morphological change.