Host: The Japanese Society of Toxicology
Nonclinical development strategies for drugs intended to be administered clinically by the topical route are generally well defined and follow principles outlined in ICH guidelines. There are, however, some additional considerations for topical drug development compared to those administered via the oral route regarding both hazard identification and risk assessment approaches. For topical drug development, the minipig is the standard nonclinical non-rodent model that is more relevant to humans and used to characterize local skin effects because of the overall similarity to human skin anatomy and physiology, while the rodent species is utilized to understand systemic risks and has limited value for understanding local skin effects since rodent skin is anatomically and functionally dissimilar to humans. Risk assessment approaches to clearly define a threshold-based toxicity in skin can be complicated by the absence of validated tools to routinely and accurately model or measure drug concentrations at specific anatomic locations within the skin, and therefore reliance on species with comparable physiology, such as minipig, is required for extrapolations based on applied dose. Exploratory methods exist for measuring drug concentrations in deep dermis of skin but understanding bioavailable concentrations of topically applied drugs closer to the site of application in the viable epidermis, the stratum basale, are not validated. This presentation will discuss challenges associated with the conduct and interpretation of topical carcinogenicity studies in rodents. Emphasis will be on the characterization and positioning of potential risk for drugs that are aneugenic in vitro but not in vivo. The presentation will offer scenarios that involve compounds with existing comprehensive systemic nonclinical data packages including oral rodent carcinogenicity data for which conduct of additional topical carcinogenicity studies in rodents may not be warranted or scientifically justified, especially considering the 3Rs. In addition, exploratory experimental data from EpiDermTM in vitro micronucleus assay will be presented as a hazard identification tool of aneugens and how it compares to the physiologically relevant in vivo minipig model.
