评估药物发育毒性的新方法方法:案例和未来方向。

IF 2.8 4区 医学 Q2 REPRODUCTIVE BIOLOGY
Nicola Powles-Glover , Allen R. Kaczor , Steven Van Cruchten , Christopher J. Bowman , Kimberly C. Brannen , Claudia Demarta-Gatsi , Isabelle LeConte , Amer Jamalpoor , Fumito Mikashima , Shermaine Mitchell-Ryan , Dinesh Stanislaus , Peter Theunissen , Belen Tornesi , Ronald L. Wange , Connie L. Chen
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引用次数: 0

摘要

制药公司正在使用几种用于发育毒性(Dev Tox)测试的新方法(NAMs)来降低风险或探索Dev Tox机制。将这些基于nams的方法用于Dev Tox风险评估的监管采用更具挑战性,部分原因是由于在整个发育过程中概念和胎盘的动态变化以及药物对母亲生理的影响,这也可能对胚胎-胎儿产生影响。尽管如此,卫生当局目前认识到,在某些使用环境下,Dev Tox NAMs可以提供足以告知风险的信息。这已在ICH S5指南的第三版中被采用,该指南为监管决策提供了一种途径来确定Dev - Tox NAMs的资格。尽管有这样的机会,制药公司很少向卫生当局提交Dev Tox名称以获得资格或意图支持监管决策。这可能部分是由于需要更好地理解目前可用的Dev Tox NAMs与体内结果、适用领域、可翻译性、预测性之间的生物学关系,并且这些NAMs没有涵盖胚胎-胎儿发育的全部范围。此外,卫生当局缺乏Dev Tox NAMs的数据可见性。为了将Dev Tox NAMs用于监管决策,需要与卫生当局共享更多数据,并进一步了解这些方法的适用范围。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
New approach methodologies for assessing developmental toxicity of pharmaceuticals: Case examples and future directions
Several new approach methodologies (NAMs) for developmental toxicity (Dev Tox) testing are being used by pharmaceutical companies for derisking or for exploring Dev Tox mechanisms. Regulatory adoption of these NAMs-based approaches as being adequate for Dev Tox risk assessment has been more challenging, due, in part, to dynamic changes in the conceptus and placenta throughout development and the impact of the pharmaceutical on the mother’s physiology, which may also have an embryo-fetal impact. Still, there is currently a recognition by Health Authorities that there are certain contexts-of-use under which Dev Tox NAMs can provide information that is adequate to inform risk. This has been adopted in the 3rd revision of the ICH S5 guideline, which provides a path to qualify Dev Tox NAMs for regulatory decision making. Despite this opportunity, pharmaceutical companies rarely submit Dev Tox NAMs to Health Authorities for qualification or with intent to support regulatory decision making. This may be in part due to the need for a greater understanding of the biological relationship between currently available Dev Tox NAMs and in vivo outcome, applicability domain, translatability, predictivity, and that these NAMs do not cover the complete scope of embryo-fetal development. Furthermore, there is a lack of Dev Tox NAMs data visibility to Health Authorities. To use Dev Tox NAMs for regulatory decision making, more data sharing with Health Authorities and further understanding the applicability domain of these methodologies are needed.
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来源期刊
Reproductive toxicology
Reproductive toxicology 生物-毒理学
CiteScore
6.50
自引率
3.00%
发文量
131
审稿时长
45 days
期刊介绍: Drawing from a large number of disciplines, Reproductive Toxicology publishes timely, original research on the influence of chemical and physical agents on reproduction. Written by and for obstetricians, pediatricians, embryologists, teratologists, geneticists, toxicologists, andrologists, and others interested in detecting potential reproductive hazards, the journal is a forum for communication among researchers and practitioners. Articles focus on the application of in vitro, animal and clinical research to the practice of clinical medicine. All aspects of reproduction are within the scope of Reproductive Toxicology, including the formation and maturation of male and female gametes, sexual function, the events surrounding the fusion of gametes and the development of the fertilized ovum, nourishment and transport of the conceptus within the genital tract, implantation, embryogenesis, intrauterine growth, placentation and placental function, parturition, lactation and neonatal survival. Adverse reproductive effects in males will be considered as significant as adverse effects occurring in females. To provide a balanced presentation of approaches, equal emphasis will be given to clinical and animal or in vitro work. Typical end points that will be studied by contributors include infertility, sexual dysfunction, spontaneous abortion, malformations, abnormal histogenesis, stillbirth, intrauterine growth retardation, prematurity, behavioral abnormalities, and perinatal mortality.
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