Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
The Guidelines for Reproductive Developmental Toxicity Testing Methods for Pharmaceuticals (ICH S5) was revised and notified in Japan (Step 5) in 2021. The following five indicators regarding the rationale for setting highest dose in the pivotal study were described in the revised guideline; 1) toxicity-based endpoint, 2) saturation of systemic exposure endpoint, 3) exposure margin based endpoint, 4) maximum feasible dose (MFD) endpoint, and 5) limit dose endpoint (1 g/kg). Regarding 3), a clear numerical standard was set for the highest dose setting as shown in the following description; "Doses providing an exposure in pregnant animals > 25-fold the exposure at the MRHD (Maximum Recommended Human Dose) are generally considered appropriate as the maximum dose for Developmental and Reproductive Toxicology studies."
In order to consider the optimal dose setting based on the revised guidelines, we investigated the highest dose in the DART study of approved drugs. The dose setting information for the embryo-fetal development (EFD) study was extracted from the CTD module 2 published on the website of PMDA, and analyzed following points; differences in the rationale for setting the highest dose depending on modality and animal species, detailed investigation of the types of toxicity that have occurred in case toxicity-based endpoint is used, calculation the margin between the exposure at the highest dose of EFD study and the exposure at MRHD, and so on. In addition to above analysis, we’d like to introduce our discussions on the optimal dose setting against the revised guideline.
