Repeated-dose ocular instillation toxicity study: a survey of its study design on the basis of common technical documents in Japan

Abstract

A repeated-dose ocular instillation toxicity study is a type of general toxicity study having unique design characteristics of species selection and administration methods, because the test article, an eye drop formulation, is instilled in the eyes. The present survey was conducted to reveal the current status of the design of repeated-dose ocular instillation toxicity studies. Information on study design was collected from the common technical documents of 21 eye-drop drugs approved in the last decade in Japan. The species most frequently employed was rabbits, followed by monkeys, then dogs. The most frequently used breed of rabbit was New Zealand white, followed by Dutch-belted. Both sexes were used in almost all the studies. In most cases, the maximum concentration of test articles was set as 3- to 10-fold higher than the clinical doses, and dosing frequency per day was set as 1.5 to 2 times the clinical usages. In many cases, a single eye of each animal was instilled with one or two drops or a fixed volume (e.g., 0.050 mL/eye in rabbits, 0.030 mL/eye in monkeys, and 0.030 to 0.100 mL/eye in dogs) of the test article. As optional ophthalmological examinations, measurements of intraocular pressure and corneal thickness were integrated frequently. In conclusion, this survey revealed design characteristics of repeated-dose ocular instillation toxicity studies, which were different in some respects from systemic dose toxicity studies. The results can be used as a baseline when considering the study design of such studies.