大学からの品質試験法提案と国際協調活動　～光安全性評価を例として～

抄録

Considerable attention has been drawn to predict a photosafety hazard on new chemicals. A number of phototoxins tend to generate reactive oxygen species (ROS) via energy transfer mechanisms following UV/VIS excitation, including superoxide and singlet oxygen. Then, ROS assay has been designed to assess photoreactivity of pharmaceuticals, of which the principle is to monitor types I and II photochemical reactions of the test chemicals when exposed to simulated sunlight. This simple analytical test could be used to screen potential chemical scaffolds, leads, and candidate drugs to identify and/or select away from those having phototoxic potential. The validation study for the ROS assay has been being carried out by the Japan Pharmaceutical Manufacturers Association (JPMA), supervised by the Japanese Center for the Validation of Alternative Methods (JaCVAM). Although several false positives appeared, the ROS assay on 42 coded chemicals has provided no false negative predictions. The validation study tentatively indicates satisfactory outcomes in terms of transferability, intra- and inter-laboratory variability, and predictive capacity. Thus, a negative result in this ROS assay would indicate a very low probability of phototoxicity, whereas a positive result would be a flag for follow-up assessment. Upon international harmonization activities supported by several agencies and industrial groups, ROS assay was successfully adopted as International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) S10 guideline (2014) and Organisation for Economic Co-operation and Development (OECD) test guideline 495 (2019).