| Autor: |
Roos P; Dutch Medicines Evaluation Board, Utrecht, the Netherlands., Anggasta C; Dutch Medicines Evaluation Board, Utrecht, the Netherlands., Piersma AH; Centre for Health Protection, Dutch Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.; Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands., van Meer PJK; Dutch Medicines Evaluation Board, Utrecht, the Netherlands.; Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands.; Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands., Theunissen PT; Dutch Medicines Evaluation Board, Utrecht, the Netherlands.; Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands. |
| Abstrakt: |
Embryofetal development (EFD) studies are performed to characterize risk of drugs in pregnant women and on embryofetal development. In line with the ICH S5(R3) guideline, these studies are generally conducted in one rodent and one non-rodent species, commonly rats and rabbits. However, the added value of conducting EFD studies in two species to risk assessment is debatable. In this study, rat and rabbit EFD studies were evaluated to analyze the added value of a second species. Information on rat and rabbit EFD studies conducted for human pharmaceuticals submitted for marketing authorization to the European Medicines Agency between 2004 and 2022 was collected from the database of the Dutch Medicines Evaluation Board, along with EFD studies conducted for known human teratogens. In total, 369 compounds were included in the database. For 55.6% of the compounds similar effects were observed in rat and rabbit EFD studies. Discordance was observed for 44.6% of compounds. Discordance could often be explained based on occurrence of maternal toxicity or the compound's mechanism of action. For other compounds, discordance was considered of limited clinical relevance due to high exposure margins or less concerning EFD toxicity. For 6.2%, discordance could not be explained and was considered clinically relevant. Furthermore, for specific therapeutic classes, concordance between rat and rabbit could vary. In conclusion, in many cases the added value of conducting EFD studies in two species is limited. These data could help identify scenarios in which (additional) EFD studies could be waived or create a weight-of-evidence model to determine the need for (additional) EFD studies. |
