放射性治疗药物的非临床安全性评价策略探讨

Discussion on nonclinical safety evaluation strategies for radiotherapeutic drugs

放射性治疗药物结构复杂,同时具有放射性、靶向性以及辐射损伤风险等,因此其非临床安全性评价应根据药物的组成结构,遵循具体问题具体分析的原则开展。本综述结合美国食品药物管理局、欧洲药品管理局颁布的放射性治疗药物相关指导原则以及《支持药物进行临床试验和上市的非临床安全性研究指导原则》,总结放射性治疗药物非临床安全性评价中药动学-毒动学、安全药理学、单次给药毒性试验、重复给药毒性试验、遗传毒性、生殖毒性、致癌性以及迟发毒性研究中需考虑的试验要点,并结合已上市的4种放射性治疗药物已开展的非临床安全性评价试验探讨放射性治疗药物的非临床安全性评价策略,为我国开展放射性治疗药物的非临床安全性评价提供参考。

Therapeutic radiopharmaceuticals are a class of in vivo radiopharmaceuticals that are widely used to treat cancers by delivering radionuclides(α particles, β particles, and γ rays) to target cells or tissues for DNA damage and kill rapidly dividing and growing cells. They have become a hot spot in drug research and development globacly. Compared with the conventional therapeutic drugs,therapeutic radiopharmaceuticals are complex in structures, radioactive, targeted and likely to cause radiation damage. Therefore, non-clinical safety evaluation of therapeutic radiopharmaceuticals should be carried out according to the composition and structure of drugs and on a case-by-case basis. This review aims to provide information about the development of non-clinical safety evaluation of therapeutic radiopharmaceuticals in China by summarizing the priorities for in the evaluation of therapeutic radiopharmaceuticals in non-clinical safety studies including pharmacokinetics-toxicokinetics, safety pharmacology,single-dose toxicity, repeated-dose toxicity, genotoxicity, reproductive toxicity, carcinogenicity, and delayed toxicity based on the guidelines issued by the US Food and Drug Administration(FDA), the European Medicines Agency(EMA) for therapeutic radiopharmaceuticals, and the Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals(ICH M3(R2))and on the strategies used in the non-clinical safety evaluation of the four types of therapeutic radiopharmaceuticals with market approval.