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Investigation of ocular events associated with taprenepag isopropyl, a topical EP2 agonist in development for treatment of glaucoma.

Authors :
Yanochko GM
Affolter T
Eighmy JJ
Evans MG
Khoh-Reiter S
Lee D
Miller PE
Shiue MH
Trajkovic D
Jessen BA
Source :
Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics [J Ocul Pharmacol Ther] 2014 Jun; Vol. 30 (5), pp. 429-39. Date of Electronic Publication: 2014 Apr 10.
Publication Year :
2014

Abstract

Purpose: Taprenepag isopropyl is an EP2 receptor agonist that is in development for the treatment of glaucoma. Iritis, photophobia, and increased corneal thickness observed in a Phase 2 clinical trial with taprenepag isopropyl were not previously observed in topical ocular toxicity studies in rabbits and dogs. In vivo studies using cynomolgus monkeys and in vitro models were used to elucidate the mechanisms underlying these ocular events.<br />Methods: Monkeys were dosed daily for 28 days in 1 eye with taprenepag and in the other with vehicle control. Complete ophthalmic examinations were performed at baseline and weekly thereafter. Serial sections of eyes were examined histopathologically at the end of the study. Recovery after the discontinuation of taprenepag was assessed for 28 days in the monkeys in the high-dose group. In vitro studies evaluated cell viability, paracellular permeability, and cytokine induction with human corneal epithelial or endothelial cell cultures.<br />Results: Monkeys demonstrated a dose-related incidence of iritis and increased corneal thickness that resolved within 28 days of discontinuing taprenepag. There was no evidence in vivo of taprenepag toxicity to the corneal endothelium or epithelium. Cell viability of stratified epithelial cells was primarily affected by excipients and was similar to Xalatan(®). The viability of HCEC-12 cells was not affected by taprenepag at concentrations up to 100 μM.<br />Conclusions: The lack of in vivo or in vitro endothelial cytotoxicity and the reversibility of the increase in corneal thickness and iritis in the monkey provide confidence to permit further clinical development of taprenepag.

Details

Language :
English
ISSN :
1557-7732
Volume :
30
Issue :
5
Database :
MEDLINE
Journal :
Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics
Publication Type :
Academic Journal
Accession number :
24720348
Full Text :
https://doi.org/10.1089/jop.2013.0222