Utility of Pre-clinical Dosimetry Evaluation in Estimating Human Absorbed Doses for First-in-Human Studies with 11C- and 18F-labeled Radiopharmaceuticals: an FDA Perspective

体内分布 剂量学 人体研究 医学物理学 核医学 医学 人类研究 内部剂量学 有效剂量(辐射) 体内 生物 心理学 内科学 生物技术 认知科学
作者
Donika Plyku,Stanley H. Stern,Hayoung Koo,Anthony F. Fotenos,Joseph G. Rajendran,K. Chakrabarti,Nyun Han,Ira Krefting,Alex Gorovets,Louis Marzella
出处
期刊:The Journal of Nuclear Medicine [Society of Nuclear Medicine and Molecular Imaging]
卷期号:62: 1561-1561
摘要

1561 Background: For radioactive drugs, 21 CFR 312.23(a)(10)(ii) requires that IND submissions include sufficient data from animal or human studies to allow a reasonable estimation of absorbed-dose (AD) to the whole-body and critical organs upon administration to a human subject. For first-in-human (FIH) studies, IND submissions include AD estimates for humans that are often extrapolated from pre-clinical (animal) biodistribution data. The extrapolation techniques make assumptions on the differences in metabolism, anatomy and biodistribution between animals and humans. However, calculation of human doses from animals is imprecise, and this presents a regulatory challenge. Two letters to the editor from Zannoti-Fregonara et al. have previously suggested pathways to assess radiation safety of 11C and 18F tracers recommending that an upper limit of injected activity for FIH studies can be derived from the max reported effective dose (ED) in humans rather than based on pre-clinical dosimetry. This study aims to gain a better understanding of the degree of uncertainty in calculations of human-organ AD and ED from animal data for 11C and 18F imaging agents. Methods: Two separate literature searches were conducted using PubMed, Embase, SciFinder and WoS for 11C and 18F radiopharmaceuticals developed since the 1990s. Articles were selected based on available human-organ dose estimates from both pre-clinical and clinical studies and analyzed according to MIRD or related methodology. FDA internal platforms were also used to retrieve information from new drug applications on 11C and 18F tracers. Human-organ AD and ED extrapolated from animal data and calculated from measurements in humans were collected from a selected number of articles. Ratios between human dose estimates derived from animals of different species and from measurements in humans were calculated. Results: The literature searches resulted in 114 (11C) and 186 (18F) articles. Dosimetry data were collected for thirteen 11C and three 18F radiotracers. The 11C radiotracers in clinical use have relatively low ED compared to 18F (range, 3.0-6.9 µSv/MBq for selected tracers), except for 11C-WAY100635 (14.1 µSv/MBq). Mean ED from clinical studies of the selected tracers was 4.6±1.1 µSv/MBq (11C) and 22±0.2 µSv/MBq (18F). The mean ratio in human ED estimate from animals to human-measured data was 1.0±0.5 (11C) and 1.0±0.2 (18F). Organs that exhibited the highest AD differ between radiotracers. The mean ratio between animal-derived and human-measured AD for human organs was: 1.1±0.6 (mouse), 1.0±0.2 (rat), 0.9±0.6 (monkey) and 1.1±0.2 (pig) for 11C; 1.0±0.5 (mouse) and 1.1±0.6 (monkey) for 18F, with AD to individual organs being both over- and under-estimated. Conclusions: In general, the ED measured in humans is quite constant across the different tracers of 11C and those of 18F, suggesting that a mean ED value from published human studies can be derived for each radioisotope. The generally modest radiation dose profile of C-11 tracers is likely due to the shorter half-life of 11C that is the major determinant of ED. The degree of over- and under-estimation in the human ED and AD values to individual human organs derived from animal biodistribution data is being analyzed to evaluate the utility of pre-clinical dosimetry for FIH trials involving short-lived PET imaging agents.[1] Zanotti-Fregonara, P., et al. (2012). EJNMMI, 39(3), 544-547[2] Zanotti-Fregonara, P., et al. (2013). EJNMMI, 40(11), 1781-1783

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
1秒前
zhui完成签到,获得积分10
2秒前
RESLR完成签到,获得积分10
3秒前
3秒前
3秒前
用户5063899发布了新的文献求助10
3秒前
5秒前
雨的痕迹完成签到,获得积分10
6秒前
Loik发布了新的文献求助10
6秒前
充电宝应助绛川采纳,获得10
6秒前
量子星尘发布了新的文献求助10
8秒前
8秒前
CAOHOU应助sue采纳,获得10
9秒前
9秒前
Loik完成签到,获得积分10
12秒前
12秒前
苗条梦玉发布了新的文献求助10
13秒前
13秒前
13秒前
18秒前
绛川发布了新的文献求助10
19秒前
momo发布了新的文献求助10
20秒前
搜集达人应助潘善若采纳,获得10
20秒前
yyer发布了新的文献求助10
21秒前
实心小墩墩完成签到,获得积分10
23秒前
28秒前
29秒前
香蕉觅云应助su采纳,获得10
29秒前
深情安青应助momo采纳,获得10
31秒前
31秒前
32秒前
可爱的函函应助hu采纳,获得10
34秒前
34秒前
35秒前
ABS发布了新的文献求助10
35秒前
36秒前
FashionBoy应助忘记时间采纳,获得30
37秒前
爆米花应助无情的匪采纳,获得10
38秒前
39秒前
刘寄奴发布了新的文献求助10
40秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989297
求助须知:如何正确求助?哪些是违规求助? 3531418
关于积分的说明 11253893
捐赠科研通 3270097
什么是DOI,文献DOI怎么找? 1804884
邀请新用户注册赠送积分活动 882087
科研通“疑难数据库(出版商)”最低求助积分说明 809158