Safety Evaluation of Ocular Drugs

Attar, Mayssa; Brassard, Jacqueline A.; Kim, Andrea S.; Matsumoto, Steven S.; Ramos, Meg Ferrell; Vangyi, Chang

doi:10.1016/b978-0-12-387815-1.00024-1

Cited by 14 publications

(20 citation statements)

References 270 publications

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“…However, the descriptions in both guidelines are concise, and do not introduce detailed design of OITSs. Overall, there is no definition of OITSs (Attar et al, 2013), and this is performed according to the ICH M3 guideline (ICH, 2009) and the ICH S4 guideline in Japan (Ministry of Health and Welfare, 1999), both being generally applied to systemic drugs.…”

Section: Purpose Of An Ocular Instillation Toxicity Studymentioning

confidence: 99%

“…The animal species is selected on a case by case basis, so that some drugs were evaluated using only one animal species (e.g., rabbits or cynomolgus monkeys). Recently, many articles have been published concerning the comparison and each feature of laboratory animals from the viewpoint of ocular safety evaluation (Atsumi et al, 2013;Attar et al, 2013;Onodera et al, 2015;Shibuya et al, 2015;Vézia, 2013). The characteristics of each species are discussed below.…”

Section: Animal Speciesmentioning

confidence: 99%

“…The frequency of topical instillation in nonclinical settings is basically high when compared to the clinical settings; e.g., 4 times/day in nonclinical compared to twice/day in clinical. High dosing frequency in OITSs is intended to obtain higher exposure multiples, especially when the maximum drug concentration is difficult to increase due to physicochemical characteristics of the test article (Attar et al, 2013). Chrai et al (1974) reported that a 5 min interval between instillations effectively increases ocular exposure in rabbits.…”

Section: Dosing Frequencymentioning

confidence: 99%

“…(2) conjunctival/scleral route (Attar et al, 2013;Regnier, 2013). Recently, from a view point of DDS to the retina/ choroid, three routes were postulated; (1) (trans-corneal) trans-vitreous route, (2) (trans-corneal) uvea-scleral route and (3) (trans-scleral) periocular route (Gadek and Lee, 2011).…”

Section: Ocular Exposurementioning

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%

See 4 more Smart Citations

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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Section: Purpose Of An Ocular Instillation Toxicity Studymentioning

confidence: 99%