Intravitreal Administration of Acetyl Triethyl Citrate and Benzyl Benzoate Is Retinotoxic in Rabbits but Not in Cynomolgus Monkeys. (April 2021)

• Record Type: Journal Article
• Authors: Andaya, Roxanne; Booler, Helen; Nagata, Denise de Almeida; Lawson, Chris; Vogt, Jennifer; Schuetz, Chris; Chang, Debby P.; Bantseev, Vladimir
• Other Names: Ramos Meg Ferrell guest-editor.; Schafer Kenneth guest-editor.; Sorden Steven guest-editor.
• Is Part Of: Toxicologic pathology. Volume 49:Number 3(2021)
• Page Start: 621
• Page End: 633
• Publication Date: 2021-04
• Subjects: intravitreal -- acetyl triethyl citrate -- benzyl benzoate -- rabbit -- cynomolgus monkey -- retinotoxicity; Pathology -- Periodicals; Toxicology -- Periodicals; Pathology; Toxicology; 615.9
• DOI: 10.1177/0192623320971571
• Languages: English
• ISSNs: 0192-6233

Abstract

Sustained drug delivery formulations are developed to reduce dose frequency while maintaining efficacy of intravitreal (ITV) administered therapeutics. Available safety data for components novel to the eye's posterior segment may be limited, requiring preclinical assessments to identify potential toxicities. We evaluated the in vivo and in vitro safety of two solvents, acetyl triethyl citrate (ATEC) and benzyl benzoate (BB), as novel sustained delivery formulations for ITV administration. In vivo tolerability was assessed following ITV administration of ATEC and BB to rabbits and cynomolgus monkeys. In rabbits, ITV solvent administration resulted in moderate to severe retinal toxicity characterized by focal retinal necrosis and/or degeneration, sometimes accompanied by inflammation, with a clear association between the physical presence of the solvent and areas of retinal damage. In contrast, solvent administration in monkeys appeared well tolerated, producing no histologic abnormalities. Toxicity in primary human retinal pigment epithelial cells, characterized by cellular toxicity and mitochondrial injury, corroborated the retinal toxicity in rabbits. In conclusion, ITV solvent depots of ATEC or BB result in chemical and focal retinal toxicity in rabbits, but not monkeys. Additional investigation is needed to demonstrate a sufficient margin of safety prior to use of ATEC or BB in ITV drug products.