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 repeateddose 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.

Histological Features of Postnatal Development of the Eye in White Rabbits

“…51 The Japanese white rabbit, employed in this study, is also used experimentally including in ocular safety evaluations. 3,52 The growth in eyeball axial length, eyeball weight, and eyeball volume; lens thickness, lens weight, and lens volume; and vitreous weight and vitreous volume are similar between New Zealand and Japanese white rabbits. 24 No apparent histological differences in the eyes from PND1 to 14 were noted between this study and previous studies on the New Zealand white rabbit.…”

“…Ophthalmic drugs are sometimes used in children. 32 When safety evaluations of ophthalmic drugs are conducted, rabbits are generally used in nonclinical toxicology studies, 1 –3 including for intravitreal injection drugs. 33,34 There are several reports of juvenile rabbits being used for toxicological evaluations for topical ocular drugs or intravitreal injection agents.…”

“…Rabbits are commonly used experimental animals for the preclinical safety assessment of ophthalmic drugs. 1 –3 Their conjunctival sac is relatively large, and drug substances can thus be easily applied to the eyes in appropriate volumes. Rabbit eyes are also larger than those of mice and rats, facilitating the evaluation of ocular irritation potentials.…”

Anatomical and histological sex differences in the eye and its accessory tissues in Dutch belted rabbits

“…Dutch rabbit is a major breed used in ocular toxicity studies (Kurata et al, 2017). In rabbits, sexual maturity occurs earlier in females than in males, and it has been reported that smaller breeds mature earlier than large ones; Dutch rabbits mature at 4 to 5 months of age and NZW rabbits mature at 5 to 7 months of age (Hillyer, 1994).…”

Pathological Features of Corneal Phospholipidosis in Juvenile White Rabbits Induced by Ocular Instillation of Chloroquine or Amiodarone

“…These formulations may affect the eyes because of their morphological or functional immaturity in children and influence the postnatal ocular development. Rabbits are generally used for safety evaluation of ophthalmic drugs (Attar et al 2013; Kurata et al 2017). An increase of Na + /K + -ATPase pump density in the rabbit corneal endothelium occurs for up to 30 days after birth (Stiemke, Edelhauser, and Geroski 1991).…”