Abstract
In 2020, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) revised the guideline for reproductive and developmental toxicity testing (S5) to allow alternative methods for embryo-fetal development studies (EFD studies). In Europe, zebrafish (ZF) embryos up to 120 hours post-fertilization (hpf) are not treated as protected animals. Thus, developmental toxicity tests using ZF embryos are advantageous in terms of animal welfare. Furthermore, due to its advantages such as histological and genetic similarity to humans/mammals, it is attracting attention as an alternative to EFD studies. However, the relationship between drug concentrations in aqueous solution (Cw) and embryonic concentrations (Ce), and the relationship with humans/mammals in terms of drug exposure related to toxicity, are unclear. In this study, we investigated the relationship between the drug exposures in ZF embryos/larvae and in humans/mammals for 21 drugs of ICH S5 positive control compounds (PCs). Analyzed with the PCs judged to be positive in ZF embryos/larvae, the area under the concentration-time curve in ZF (zAUC) based on the estimated drug concentrations in embryos/larvae showed a good correlation with the area under the blood concentration-time curve (AUC) in humans, rats, and rabbits. This result indicates that the exposure level causing developmental toxicity by each drug was similar between ZF embryos and humans/mammals.
