Nonclinical Regulatory Aspects for Ophthalmic Drugs

Weir, Andrea B.; Wilson, Susan

doi:10.1007/978-1-62703-164-6_7

Cited by 9 publications

(17 citation statements)

References 8 publications

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“…The other species used are monkeys and dogs, which are non-rodent species. The reason these non-rodents are selected is probably because their ocular size is appropriate for eye drop instillation and ophthalmological examinations (Attar et al, 2013;Weir and Wilson, 2013). This is different from the species selection in general toxicity studies of drugs having systemic administration routes (oral and intravenous routes, etc.…”

Section: Discussionmentioning

confidence: 99%

“…In the USA, the Food and Drug Administration (FDA) has issued a draft guideline regarding nonclinical safety evaluation of reformulated drug products and products intended for administration by an alternate route, including ocular routes (FDA/CDER, 2008). Several reviews and books regarding ocular toxicology studies have been also published, including its methodology (Attar et al, 2013;Kurata et al, 2016;Short, 2008;Weir and Wilson, 2013). However, to our knowledge, there is still little information available regarding detailed design features of OITSs.…”

Section: Introductionmentioning

confidence: 99%

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

Kurata

Yamagiwa

Haranosono

et al. 2017

Fundam. Toxicol. Sci.

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-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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Kurata

Yamagiwa

Haranosono

et al. 2017

Fundam. Toxicol. Sci.

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“…However, as the drug is administered directly to the eyes, ophthalmologic examinations are more detailed and include more platforms in OITSs. Weir and Wilson (2013) described the following examinations as an example of the standard endpoints for ocular safety in nonclinical ocular toxicity studies; gross observation, slip lamp biomicroscopy, funduscopy, tonometry, electroretinography and histopathology.…”

Section: Examinations For Ocular and Accessory Tissues Routine/standamentioning

confidence: 99%

“…Assessment of systemic toxicities in OITSs is basically the same as in general toxicity studies of drugs administered via systemic routes. Weir and Wilson (2013) described the following examinations as systemic end-points in ocular toxicity studies; clinical observation, body weight, food consumption, clinical pathology, necropsy, organ weights, histopathology, toxicokinetics (TK) and immunogenicity (biologics). Based on our knowledge and experiences, systemic examinations in the in-life stage (excluding ophthalmologic examinations described in the previous section) are summarized in Table 5.…”

Section: Examinations For Systemic Organsmentioning

confidence: 99%

“…Recently, several excellent reviews and books have been published regarding ocular toxicology including its methodology, safety evaluation and development issues (Attar et al, 2013;Onodera et al, 2015;Short, 2008;Shibuya et al, 2015;Weir and Wilson, 2013). However, the articles focusing on OITSs and related information are generally limited in number.…”

Section: Introductionmentioning

confidence: 99%

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Ocular instillation toxicity study: current status and points to consider on study design and evaluation

Kurata

Atsumi

Yamagiwa

et al. 2016

Fundam. Toxicol. Sci.

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Ocular instillation toxicity studies (OITSs) are one of general toxicity studies. Yet, OITSs have a unique characteristic that the test article is directly administered as eye drops to the target organ. Compared with general toxicity studies aiming systemic exposure, the study design of OITSs is somewhat distinctive in selecting test species, dosing formulation, administration volume/frequency and ocular examinations. After the administration of eye drops, the exposure level is high in the ocular surface, whereas the bioavailability in the eye balls, especially in the posterior segment, is low. In contrast to the general toxicity studies aiming systemic exposure, the absolute systemic exposure level in OITSs is generally low, while the systemic bioavailability is relatively high. These pharmacokinetic features determine the profiles of local and systemic toxicities in OITSs. Systemic toxicities are more often found in animals of relatively small body size, and are in most cases related with pharmacological actions. Current progress in ophthalmologic imaging technologies enables advanced safety evaluation using imaging biomarkers. Bioanalysis detecting drug levels present in blood in trace amount leads to a detailed safety assessment of systemic toxicity and yields accurate safety margins. Recognizing the peculiar characteristics of OITSs, toxicologists need to propose an appropriate study design and strategy of safety evaluation. Further discussion may be awaited on rationales for testing both sexes, and for conducting separated toxicity studies to evaluate systemic toxicity. This mini-review provides insight regarding current status and points to consider of OITSs.

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Ocular Toxicity Regulatory Considerations for Nondrug Food and Drug Administration (FDA) Products and the Environmental Protection Agency (EPA)

Bartlett¹

2012

Assessing Ocular Toxicology in Laboratory Animals

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Nonclinical Regulatory Aspects for Ophthalmic Drugs

Cited by 9 publications

References 8 publications

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

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

Ocular instillation toxicity study: current status and points to consider on study design and evaluation

Ocular Toxicity Regulatory Considerations for Nondrug Food and Drug Administration (FDA) Products and the Environmental Protection Agency (EPA)

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