Human Relevance of Pharmaceutical Drug-Induced Thyroid Tumors in Rats, Labeling Implications, and Carcinogenicity Study Requirements.

IF 2.7 4区 医学 Q3 TOXICOLOGY Journal of Applied Toxicology Pub Date : 2025-03-13 DOI:10.1002/jat.4779
B D Hollingshead, Z A Radi
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Abstract

In rats, thyroid tumors are common age-related findings with reported incidence rates up to 8.1% and 11.86% for follicular and C-cell adenomas, respectively. Increases of thyroid follicular neoplasms in rodents via the induction of hepatic UDP-glucuronosyltransferase (UGT) enzymes, resulting in elevated thyroid hormone (TH) metabolism, excretion, and subsequent follicular cell proliferation are generally accepted to have little or no relevance to humans due to species differences in sensitivity to this pathophysiologic process. In this analysis, we reviewed approved drugs that resulted in thyroid tumors in 2-year rat carcinogenicity studies and summarized the positioning of these findings in product labeling language and human risk assessments in the United States and Europe. Overall, although thyroid follicular cell tumors are commonly observed, the labels reviewed listed no suspected human risk or directly state the absence of human relevance for these findings. Like follicular cell tumors, thyroid C-cell tumors are common background findings in rats but comparatively are not as commonly increased in frequency as drug-related findings in 2-year rodent carcinogenicity studies. These findings are most notably observed with GLP-1 agonists and their human relevance is a topic of ongoing clinical safety surveillance analysis. Thyroid follicular cell hyperplasia, when specifically occurring through hepatic enzyme induction and/or enhanced TH clearance, should be evaluated for anticipated human translational relevance using nonclinical and clinical data. If no human relevance is anticipated, this rationale should be incorporated into a weight of evidence approach for carcinogenicity studies as outlined in the ICH S1B addendum.

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在大鼠体内,甲状腺肿瘤是一种常见的与年龄有关的疾病,据报道,滤泡腺瘤和C细胞腺瘤的发病率分别高达8.1%和11.86%。啮齿类动物的甲状腺滤泡肿瘤是通过诱导肝脏 UDP-葡萄糖醛酸转移酶(UGT)酶,导致甲状腺激素(TH)代谢、排泄和随后的滤泡细胞增殖升高而增加的,由于物种对这一病理生理过程的敏感性不同,人们普遍认为这与人类关系不大或没有关系。在本分析中,我们回顾了在为期 2 年的大鼠致癌性研究中导致甲状腺肿瘤的已批准药物,并总结了这些发现在美国和欧洲的产品标签语言和人体风险评估中的定位。总体而言,尽管甲状腺滤泡细胞瘤很常见,但所审查的标签并未列出疑似的人体风险,或直接说明这些结果与人体无关。与滤泡细胞瘤一样,甲状腺 C 细胞瘤在大鼠中也是常见的背景发现,但在为期 2 年的啮齿动物致癌性研究中,与药物相关的发现频率相对没有那么高。这些发现在 GLP-1 激动剂中最为明显,其与人体的相关性是正在进行的临床安全性监测分析的一个主题。如果甲状腺滤泡细胞增生是通过肝酶诱导和/或甲状腺激素清除率升高而发生的,则应使用非临床和临床数据对其预期的人体转化相关性进行评估。如果预计与人类无关,则应将这一理由纳入 ICH S1B 增补中概述的致癌性研究证据权重法。
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来源期刊
CiteScore
7.00
自引率
6.10%
发文量
145
审稿时长
1 months
期刊介绍: Journal of Applied Toxicology publishes peer-reviewed original reviews and hypothesis-driven research articles on mechanistic, fundamental and applied research relating to the toxicity of drugs and chemicals at the molecular, cellular, tissue, target organ and whole body level in vivo (by all relevant routes of exposure) and in vitro / ex vivo. All aspects of toxicology are covered (including but not limited to nanotoxicology, genomics and proteomics, teratogenesis, carcinogenesis, mutagenesis, reproductive and endocrine toxicology, toxicopathology, target organ toxicity, systems toxicity (eg immunotoxicity), neurobehavioral toxicology, mechanistic studies, biochemical and molecular toxicology, novel biomarkers, pharmacokinetics/PBPK, risk assessment and environmental health studies) and emphasis is given to papers of clear application to human health, and/or advance mechanistic understanding and/or provide significant contributions and impact to their field.
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