Evaluation of rat and rabbit embryofetal development studies with pharmaceuticals: the added value of a second species.

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.

The use of weight-of-evidence approaches to characterize developmental toxicity risk for therapeutic monoclonal antibodies in humans without in vivo studies.

Regulatory guidance for global drug development relies on animal studies to evaluate safety risks for humans, including risk of reproductive toxicity. Weight-of-evidence approaches (WoE) are increasingly becoming acceptable to evaluate risk. A WoE for developmental risk of monoclonal antibodies (mAbs) was evaluated for its ability to retrospectively characterize risk and to determine the need for further in vivo testing based on the remaining uncertainty. Reproductive toxicity studies of 65 mAbs were reviewed and compared to the WoE. Developmental toxicities were absent in 52/65 (80%) mAbs. Lack of toxicity was correctly predicted in 29/52 (56%) cases. False positive and equivocal predictions were made in 9/52 (17%) and 14/52 (27%) cases. For 3/65 (5%) mAbs, the findings were equivocal. Of mAbs with developmental toxicity findings (10/65, 15%), the WoE correctly anticipated pharmacology based reproductive toxicity without any false negative predictions in 9/10 (90%) cases, and in the remaining case (1/10, 10%) an in vivo study was recommended due to equivocal WoE outcome. Therefore, this WoE approach could characterize presence and absence of developmental risk without animal studies. The current WoE could have reduced the need for developmental toxicity studies by 42% without loss of important patient information in the label.

Polymer Stereocomplexation as a Scalable Platform for Nanoparticle Assembly.

DNA-mediated assembly of inorganic particles has demonstrated to be a powerful approach for preparing nanomaterials with a range of interesting optical and electrical properties. Building on this inspiration, we describe a generalizable gram-scale method to assemble nanoparticles through the formation of poly(methyl methacrylate) (PMMA) triple-helices. In this work, alkene-terminated syndiotactic (st-) and isotactic (it-) PMMA polymers were prepared and subsequently functionalized to afford nanoparticle ligands. Nanoparticles with complementary st- and it-PMMA ligands could then be spontaneously assembled upon mixing at room temperature. This process was robust and fully reversible through multiple heating and cooling cycles. The versatility of PMMA stereocomplexation was highlighted by assembling hybrid structures composed of nanoparticles of different compositions (e.g., Au and quantum dots) and shapes (e.g., spheres and rods). These initial demonstrations of nanoparticle self-assembly from inexpensive PMMA-based materials present an attractive alternative to DNA-based nanomaterials.