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Commentary: Understanding IARC's PFOA and PFOS carcinogenicity assessments 评论:了解 IARC 的 PFOA 和 PFOS 致癌性评估。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-10-19 DOI: 10.1016/j.yrtph.2024.105726
Nicholas L. Drury , Robyn L. Prueitt , Barbara D. Beck
In November 2023, the International Agency for Research on Cancer (IARC) classified PFOA as “carcinogenic to humans” (Group 1) and PFOS as “possibly carcinogenic to humans” (Group 2B). We evaluated these classifications, considering the epidemiology, experimental animal, and mechanistic evidence. It is our opinion that the IARC Working Group overstated the available evidence for the carcinogenicity of PFOA and PFOS. Epidemiology studies have shown weak and inconsistent associations across studies. Studies reporting increased incidences of tumors in experimental animals exposed to PFOA or PFOS had statistically significant results that were driven by the presence of benign adenomas. The IARC Working Group used the key characteristics of carcinogens (KCCs, which comprise 10 chemical and/or biological properties of known human carcinogens) approach to upgrade the carcinogenicity classifications for PFOA and PFOS from initially lower classifications that were based on the strength of the epidemiology and experimental animal evidence. However, this is not a robust assessment of mechanistic evidence, as it fails to consider the quality, external validity, and relevance of the evidence. Rather than use the KCCs as a checklist of potential carcinogenic mechanisms, IARC should use a rigorous method to evaluate the plausibility and human relevance of mechanistic evidence.
2023 年 11 月,国际癌症研究机构(IARC)将全氟辛烷磺酸列为 "对人类致癌"(第 1 类),将全氟辛烷磺酸列为 "可能对人类致癌"(第 2B 类)。我们对这些分类进行了评估,考虑了流行病学、实验动物和机理证据。我们认为,国际癌症研究机构工作组夸大了 PFOA 和 PFOS 致癌的现有证据。流行病学研究表明,不同研究之间的关联性较弱且不一致。报告暴露于全氟辛烷磺酸或全氟辛烷磺酸的实验动物肿瘤发病率增加的研究,其结果在统计学上具有显著意义,这是因为良性腺瘤的存在。国际癌症研究机构工作组采用致癌物关键特征(KCCs,由已知人类致癌物的 10 种化学和/或生物特性组成)的方法,将 PFOA 和 PFOS 的致癌性分类从最初的较低分类升级,而最初的较低分类是基于流行病学和实验动物证据的强度。然而,这并不是对机理证据的有力评估,因为它没有考虑证据的质量、外部有效性和相关性。国际癌症研究机构不应将 KCCs 用作潜在致癌机制的核对表,而应使用严格的方法来评估机理证据的合理性和与人类的相关性。
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引用次数: 0
An analysis of the use of historical control data in the assessment of regulatory pesticide toxicity studies 分析历史控制数据在农药毒性监管研究评估中的应用。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-10-18 DOI: 10.1016/j.yrtph.2024.105724
Jürg A. Zarn, Sebastian L.B. König, Holly V. Shaw, H. Christoph Geiser
The concurrent control group is the most important reference for the interpretation of toxicity studies. However, pooled information on control animals from independent studies, i.e., historical control data (HCD), is also used for the interpretation of results. Currently, an overview on actual HCD use in regulatory toxicology is lacking. Therefore, we evaluated the HCD use of the Joint FAO/WHO Meeting on Pesticide Residues from 2004 to 2021 and compared it with recommendations in regulatory guidelines and in the literature. We found that HCD was used routinely and exclusively to avoid potential false positive decisions regarding the treatment-relatedness of effects, mostly using the HCD range, i.e., the most extreme values, as a benchmark. HCD were not used to avoid potential false negative decisions or for quality control of the index study. The central assumption of the HCD use, namely that the HCD and control group of the index study follow the same underlying distribution because they are samples of the same data generation process, was not investigated, although numerous factors potentially contribute to effect variation between the different control groups pooled in the HCD. We recommend that the existing guidelines be revised to improve the robustness and transparency of toxicological assessments.
同期对照组是解释毒性研究的最重要参考。不过,来自独立研究的对照动物的汇总信息,即历史对照数据(HCD),也可用于解释研究结果。目前,监管毒理学中实际使用 HCD 的情况尚缺乏综述。因此,我们评估了 2004 年至 2021 年粮农组织/世卫组织农药残留联席会议使用 HCD 的情况,并将其与监管指南和文献中的建议进行了比较。我们发现,HCD 的常规使用完全是为了避免在影响的处理相关性方面可能出现的假阳性判定,大多使用 HCD 范围(即最极端值)作为基准。HCD 不用于避免潜在的假阴性判定,也不用于指标研究的质量控制。使用 HCD 的核心假设,即指数研究中的 HCD 和对照组遵循相同的基本分布,因为它们是同一数据生成过程中的样本,并没有进行调查,尽管有许多因素可能导致 HCD 中汇集的不同对照组之间的效应差异。我们建议修订现有指南,以提高毒理学评估的稳健性和透明度。
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引用次数: 0
In vivo micronucleus assay on sodium molybdate in rats and its impact on the overall assessment of the genotoxicity of molybdenum substances 钼酸钠大鼠体内微核试验及其对全面评估钼物质遗传毒性的影响。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-10-11 DOI: 10.1016/j.yrtph.2024.105717
Sue A. Hubbard , Kevin Klipsch , Michael S. Cockburn , Sandra Carey
In this paper we present methodological and experimental details and results from an OECD Test Guideline 474 and GLP-compliant in vivo micronucleus study on sodium molybdate dihydrate in Sprague Dawley rats. Prior to the conduct of this study, there was a data-gap for reliable in vivo genotoxicity data for molybdenum substances. The presentation of the new study is complemented by a review of other available in vitro and in vivo data on the genotoxicity of molybdenum substances, focussing on substances where the contained or released molybdate ion, MoO42−, is considered the responsible moiety for any toxicological effect (grouping/category approach). After consideration of the relevance and reliability of all available data, the absence of a concern for genotoxicity of molybdate in vitro and in vivo is concluded.
本文介绍了一项符合《经合组织测试指南 474》和 GLP 标准的体内微核试验研究的方法和实验细节,以及在 Sprague Dawley 大鼠体内对钼酸钠二水合物进行的研究结果。在开展这项研究之前,关于钼物质的可靠体内遗传毒性数据还存在空白。在介绍这项新研究的同时,我们还回顾了有关钼物质遗传毒性的其他现有体外和体内数据,重点是那些含有或释放的钼酸根离子MoO42-被认为是造成任何毒理效应的主要分子的物质(分组/分类方法)。在考虑了所有可用数据的相关性和可靠性后,得出结论认为钼酸盐在体外和体内不存在遗传毒性问题。
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引用次数: 0
Analysis of implicit and explicit uncertainties in QSAR prediction of chemical toxicity: A case study of neurotoxicity 化学毒性 QSAR 预测中的隐式和显式不确定性分析:神经毒性案例研究。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-10-10 DOI: 10.1016/j.yrtph.2024.105716
Jerry Achar , James W. Firman , Chantelle Tran , Daniella Kim , Mark T.D. Cronin , Gunilla Öberg
Although uncertainties expressed in texts within QSAR studies can guide quantitative uncertainty estimations, they are often overlooked during uncertainty analysis. Using neurotoxicity as an example, this study developed a method to support analysis of implicitly and explicitly expressed uncertainties in QSAR modeling studies. Text content analysis was employed to identify implicit and explicit uncertainty indicators, whereafter uncertainties within the indicator-containing sentences were identified and systematically categorized according to 20 uncertainty sources. Our results show that implicit uncertainty was more frequent within most uncertainty sources (13/20), while explicit uncertainty was more frequent in only three sources, indicating that uncertainty is predominantly expressed implicitly in the field. The most highly cited sources included Mechanistic plausibility, Model relevance and Model performance, suggesting they constitute sources of most concern. The fact that other sources like Data balance were not mentioned, although it is recognized in the broader QSAR literature as an area of concern, demonstrates that the output from the type of analysis conducted here must be interpreted in the context of the broader QSAR literature before conclusions are drawn. Overall, the method established here can be applied in other QSAR modeling contexts and ultimately guide efforts targeted towards addressing the identified uncertainty sources.
虽然 QSAR 研究中文本表达的不确定性可以指导定量不确定性估计,但在不确定性分析过程中却经常被忽视。本研究以神经毒性为例,开发了一种支持分析 QSAR 建模研究中隐含和明确表达的不确定性的方法。我们采用文本内容分析法来识别隐式和显式不确定性指标,然后识别包含指标的句子中的不确定性,并根据 20 个不确定性来源进行系统分类。结果表明,在大多数不确定性来源(13/20)中,隐式不确定性更为常见,而显式不确定性仅在三个来源中更为常见,这表明不确定性在该领域主要以隐式表达。引用率最高的来源包括机理可信性、模型相关性和模型性能,这表明它们是最受关注的来源。数据平衡等其他来源虽然在更广泛的 QSAR 文献中被认为是一个值得关注的领域,但却没有被提及,这一事实表明,在得出结论之前,必须在更广泛的 QSAR 文献背景下对本文所做分析的结果进行解释。总之,本文所建立的方法可用于其他 QSAR 建模环境,并最终指导解决已确定的不确定性来源。
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引用次数: 0
Selection of solvent and positive control concentration for enhanced Ames test conditions for N-nitrosamine compounds 针对 N-亚硝胺化合物的强化 Ames 试验条件,选择溶剂和阳性对照浓度
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-10-10 DOI: 10.1016/j.yrtph.2024.105711
Chetan K. Kajavadara, Satyam N. Patel, Rushikesh M. Shukla, Darshan T. Valani, Rajesh J. Patel, Laxit K. Bhatt, Rajesh Sundar, Mukul R. Jain
The Ames test is a widely used bacterial mutagenicity assay to evaluate the potential of chemical compounds to induce mutations. In recent years, there has been growing concern regarding the presence of N-nitrosamines in pharmaceuticals, food, and other consumer products. N-Nitrosamines are probable mutagens and carcinogens. To address the reduced sensitivity of the standard Ames test for N-nitrosamines, particularly N-nitrosodimethylamine, the European Medicines Agency (EMA) and United States Food and Drug Administration (FDA) have recently published recommendations for enhanced Ames test (EAT) conditions. However, there is a lack of clear guidance on the selection of N-nitrosamine positive control concentrations, particularly for 1-cyclopentyl-4-nitrosopiperazine, and the amount of solvent to be used in the EAT. This study aims to address the current gap in concentration and volume specifications by providing a comprehensive guide to set up enhanced Ames test conditions specifically for N-nitrosamine compounds using appropriate amounts of solvent, new solvents, and strain-specific positive control concentrations.
艾姆斯试验是一种广泛使用的细菌诱变性检测方法,用于评估化学物质诱发突变的可能性。近年来,人们越来越关注药品、食品和其他消费品中是否含有 N-亚硝胺。亚硝胺可能是诱变剂和致癌物质。为了解决亚硝胺(尤其是 N-亚硝基二甲胺)标准阿姆斯试验灵敏度降低的问题,欧洲药品管理局 (EMA) 和美国食品药品管理局 (FDA) 最近公布了关于增强型阿姆斯试验 (EAT) 条件的建议。然而,在选择 N-亚硝胺阳性对照浓度(尤其是 1-环戊基-4-亚硝基哌嗪)和 EAT 中使用的溶剂量方面缺乏明确的指导。本研究旨在解决目前在浓度和体积规范方面的空白,提供一份综合指南,指导如何使用适当的溶剂量、新溶剂和特定菌株的阳性对照浓度,专门针对 N-亚硝胺化合物建立增强型艾姆斯试验条件。
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引用次数: 0
Safety assessment of drug impurities for patient safety: A comprehensive review 针对患者安全的药物杂质安全评估:全面综述。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-10-05 DOI: 10.1016/j.yrtph.2024.105715
Frank Liu
Drug impurities are undesirable but unavoidable chemicals which can occur throughout the drug life cycle. The safety implications of drug impurities can be significant given that they can impact safety, quality, and efficacy of drug products and that certain drug impurities are mutagenic, carcinogenic, or teratogenic. The characteristics of drug impurities could be specific to drug modalities (e.g., small molecules vs. biologics). The commonly encountered drug impurities include elemental impurity, residual solvent, organic impurity, host cell protein and DNA, residual viral vector, extractable and leachable, and particle. They can cause various adverse effects such as immunogenicity, infection, genotoxicity, and carcinogenicity upon significant exposure. Therefore, the effective control of these drug impurities is central for patient safety. Regulations and guidelines are available for drug developers to manage them. Their qualification is obtained based on authoritative qualification thresholds or safety assessment following the classic toxicological risk assessment. The current review focuses on the safety assessment science and methodology used for diverse types of drug impurities. Due to the different nature of diverse drug impurities, their safety assessment represents a significant challenge for drug developers.
药物杂质是在整个药物生命周期中可能出现的不良但不可避免的化学物质。鉴于药物杂质会影响药物产品的安全、质量和疗效,而且某些药物杂质具有致突变、致癌或致畸作用,因此药物杂质对安全的影响可能非常大。药物杂质的特征可能因药物方式(如小分子药物与生物制剂)而异。常见的药物杂质包括元素杂质、残留溶剂、有机杂质、宿主细胞蛋白和 DNA、残留病毒载体、可提取和可浸出物以及颗粒。这些杂质一旦大量接触,就会产生各种不良反应,如免疫原性、感染、基因毒性和致癌性。因此,有效控制这些药物杂质对患者安全至关重要。目前已有相关法规和指南供药物开发商管理这些杂质。它们的合格性是根据权威的合格阈值或按照经典的毒理学风险评估进行的安全性评估而获得的。本综述重点关注用于不同类型药物杂质的安全性评估科学和方法。由于各种药物杂质的性质不同,其安全性评估对药物开发人员来说是一项重大挑战。
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引用次数: 0
Quantitative risk assessments of skin sensitization for 26 allergens in different consumer products in the Saudi market 对沙特市场不同消费品中的 26 种过敏原进行皮肤过敏定量风险评估。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-10-03 DOI: 10.1016/j.yrtph.2024.105714
Adnan S. AL-Mussallam , Rawan S. Alshathri , Bart Desmedt , Fahad S. Aldawsari , Eric Deconinck , Omniyah A. Alharthi , Abdullah T. Bawazir
Fragrance chemicals are ubiquitous in cosmetics; however, they have been linked to allergic contact dermatitis. Allergy prevention involves two main strategies. Firstly, consumers are protected by limiting the maximum concentration of fragrance in a given product to avoid inducing allergies. Secondly, consumers who are already sensitized are protected by having the presence of such fragrance communicated to them. In this study, a validated GC-MS method was employed to quantify 26 allergens in 108 products marketed in Saudi Arabia.Additionally, a quantitative risk assessment (QRA) was performed on the studied cosmetics to determine the risk of inducing allergies. The results indicated that most allergens were present at acceptable concentrations, while 19 products carried a risk of inducing allergies. Furthermore, Lilial and Lyral, two prohibited fragrances, were detected in 97 products. It should be emphasized that this is the first study conducted in Saudi Arabia to evaluate the safety of the well-known 26 fragrance allergens. Hence, this study can potentially serve as a regional standard for future research.
香料化学物质在化妆品中无处不在,但它们却与过敏性接触性皮炎有关。预防过敏主要有两种策略。首先,通过限制特定产品中香料的最大浓度来保护消费者,避免诱发过敏。其次,对于已经过敏的消费者,可以通过告知他们产品中含有此类香料来保护他们。此外,还对所研究的化妆品进行了定量风险评估 (QRA),以确定诱发过敏的风险。结果表明,大多数过敏原的浓度在可接受范围内,而 19 种产品有诱发过敏的风险。此外,在 97 种产品中检测到了 Lilial 和 Lyral 这两种禁用香料。需要强调的是,这是沙特阿拉伯首次对众所周知的 26 种香料过敏原的安全性进行评估。因此,这项研究有可能成为未来研究的地区标准。
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引用次数: 0
Mapping new psychoactive substances: Leveraging GIS technology for advanced global surveillance and policy support 绘制新型精神活性物质地图:利用 GIS 技术进行先进的全球监控和政策支持。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-10-02 DOI: 10.1016/j.yrtph.2024.105713
Ting-Jung Ku , Tien-Chueh Kuo , Olivia A. Lin , Yufeng Jane Tseng
The escalating challenge of New Psychoactive Substances (NPS) necessitates enhanced global monitoring and analysis capabilities. This study introduces an advanced interactive visualization tool that employs Geographic Information System (GIS) technologies to improve the functionality of the UNODC's Early Warning Advisory. The tool enables dynamic observation and analysis of NPS's geographical and temporal distribution, thereby facilitating a comprehensive understanding of their public health impacts. By incorporating detailed choropleth maps and annual and cumulative bar charts, the tool allows policymakers and researchers to visually track and analyze trends in NPS usage and control efforts across different regions. The results demonstrate the tool's effectiveness in providing actionable insights, which support the strategic development of public health policies and interventions to curb the global rise in NPS usage. This initiative illustrates the essential role of digital tools in enhancing public health strategies and responses to emerging drug trends. This rising challenge underscores the urgent need for innovative solutions in monitoring drug trends, a theme explored in this paper. The web tool is available at https://nps-vis.cmdm.tw, and the code is available at https://github.com/CMDM-Lab/nps-vis.
新型精神活性物质(NPS)的挑战不断升级,需要加强全球监测和分析能力。本研究介绍了一种先进的交互式可视化工具,该工具利用地理信息系统(GIS)技术改进了毒品和犯罪问题办公室预警咨询的功能。该工具可对核动力源的地理和时间分布进行动态观察和分析,从而有助于全面了解其对公共健康的影响。通过纳入详细的纵横图以及年度和累积条形图,该工具使政策制定者和研究人员能够直观地跟踪和分析不同地区的 NPS 使用和控制工作的趋势。结果表明,该工具在提供可操作的见解方面非常有效,有助于战略性地制定公共卫生政策和干预措施,以遏制全球非兴奋剂使用率的上升。这一举措说明了数字工具在加强公共卫生战略和应对新兴毒品趋势方面的重要作用。这一日益严峻的挑战凸显了在监测毒品趋势方面对创新解决方案的迫切需求,这也是本文探讨的主题。网络工具见 https://nps-vis.cmdm.tw,代码见 https://github.com/CMDM-Lab/nps-vis。
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引用次数: 0
Optimizing the detection of N-nitrosamine mutagenicity in the Ames test 优化艾姆斯试验中 N-亚硝胺致突变性的检测。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-09-28 DOI: 10.1016/j.yrtph.2024.105709
Robert H. Heflich , Michelle E. Bishop , Roberta A. Mittelstaedt , Jian Yan , Sharon K. Guerrero , Audrey M. Sims , Kamela Mitchell , Nyosha Moore , Xilin Li , Nan Mei , Rosalie K. Elespuru , Sruthi T. King , David A. Keire , Naomi L. Kruhlak , Robert T. Dorsam , Andre S. Raw , Karen L. Davis Bruno , Timothy J. McGovern , Aisar H. Atrakchi
Accurately determining the mutagenicity of small-molecule N-nitrosamine drug impurities and nitrosamine drug substance-related impurities (NDSRIs) is critical to identifying mutagenic and cancer hazards. In the current study we have evaluated several approaches for enhancing assay sensitivity for evaluating the mutagenicity of N-nitrosamines in the bacterial reverse mutagenicity (Ames) test. Preincubation assays were conducted using five activation conditions: no exogenous metabolic activation and metabolic activation mixes employing both 10% and 30% liver S9 from hamsters and rats pretreated with inducers of enzymatic activity. In addition, preincubations were conducted for both 60 min and 30 min. These test variables were evaluated by testing 12 small-molecule N-nitrosamines and 17 NDSRIs for mutagenicity in Salmonella typhimurium tester strains TA98, TA100, TA1535, and TA1537, and Escherichia coli strain WP2 uvrA (pKM101). Eighteen of the 29 N-nitrosamine test substances tested positive under one or more of the testing conditions and all 18 positives could be detected by using tester strains TA1535 and WP2 uvrA (pKM101), preincubations of 30 min, and S9 mixes containing 30% hamster liver S9. In general, the conditions under which NDSRIs were mutagenic were similar to those found for small-molecule N-nitrosamines.
准确测定小分子 N-亚硝胺药物杂质和亚硝胺药物物质相关杂质(NDSRIs)的诱变性对于确定诱变和癌症危害至关重要。在目前的研究中,我们评估了几种提高测定灵敏度的方法,以评估细菌反向诱变性(艾姆斯)试验中 N-亚硝胺的诱变性。使用五种活化条件进行了预孵育试验:无外源代谢活化和代谢活化混合液,其中混合液采用了用酶活性诱导剂预处理过的仓鼠和大鼠 10% 和 30% 的肝脏 S9。此外,还进行了 60 分钟和 30 分钟的预孵育。通过在鼠伤寒沙门氏菌试验菌株 TA98、TA100、TA1535 和 TA1537 以及大肠杆菌菌株 WP2 uvrA(pKM101)中测试 12 种小分子 N-亚硝胺和 17 种 NDSRI 的诱变性,对这些测试变量进行了评估。在 29 种 N-亚硝胺测试物质中,有 18 种在一种或多种测试条件下呈阳性,使用测试菌株 TA1535 和 WP2 uvrA (pKM101)、预培养 30 分钟以及含有 30% 仓鼠肝脏 S9 的 S9 混合物,可检测到所有 18 种阳性物质。一般来说,NDSRIs 诱变条件与小分子 N-亚硝胺的诱变条件相似。
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引用次数: 0
Rethinking the necessity of long-term toxicity studies for biotherapeutics using weight of evidence assessment 利用证据权重评估重新思考生物治疗药物长期毒性研究的必要性。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-09-26 DOI: 10.1016/j.yrtph.2024.105710
Payal Rana , Brett Hollingshead , Raja Mangipudy
The registration of biotherapeutics for chronic indications requires 6-month toxicity studies. However, extensive experience has shown that the non-clinical safety profiles of biotherapeutics are generally predictable. This suggests that conducting multiple studies, especially a 6-month study may not be necessary. In a meta-analysis of biologics developed for non-oncology indications over last 25 years at Pfizer, we compared organ system findings between short-term (1–3 month) and long-term (6-month) animal studies. Our goal was to determine if there were differences in the safety profiles between the two study durations and their relevance to human risk assessment. Our analysis revealed that most clinically relevant toxicities could be detected in shorter-term studies (87%; 26/30 programs). This suggests either an undifferentiated safety profile between short-and long-term studies, or anticipated toxicities based on the modality, such as immunogenicity or exaggerated pharmacology. However, for 4 out of 30 programs (13%), long-term studies did identify either potential new toxicities or more severe manifestation of exaggerated pharmacology, leading to modifications in clinical trial designs and human risk assessment. Our experience suggests that 3-month toxicity studies may be sufficient to support late-stage clinical development for a majority of standard biotherapeutic programs. This pragmatic and science-based approach aligns with the goal of advancing 3R's initiatives in nonclinical safety assessment.
慢性适应症生物疗法的注册要求进行为期 6 个月的毒性研究。然而,丰富的经验表明,生物治疗药物的非临床安全性概况通常是可以预测的。这表明,进行多项研究,尤其是为期 6 个月的研究可能并无必要。在辉瑞公司过去 25 年针对非肿瘤适应症开发的生物制剂的荟萃分析中,我们比较了短期(1-3 个月)和长期(6 个月)动物研究的器官系统结果。我们的目标是确定两种研究期限的安全性是否存在差异,以及它们与人体风险评估的相关性。我们的分析表明,大多数与临床相关的毒性可在短期研究中检测到(87%;26/30 个项目)。这表明,短期和长期研究的安全性特征并无差别,或者是基于模式的预期毒性,如免疫原性或夸大的药理作用。不过,在 30 个项目中,有 4 个项目(13%)的长期研究确实发现了潜在的新毒性或更严重的夸大药理表现,从而导致临床试验设计和人体风险评估的修改。我们的经验表明,3 个月的毒性研究可能足以支持大多数标准生物治疗项目的后期临床开发。这种以科学为基础的务实方法与推进 3R 计划的目标不谋而合。
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引用次数: 0
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