吸入药物非临床毒性评价特点与要求

doi:10.19803/j.1672-8629.2021.06.16

中国药物警戒 ›› 2021, Vol. 18 ›› Issue (6): 570-574.
DOI: 10.19803/j.1672-8629.2021.06.16

吸入药物非临床毒性评价特点与要求

张海飞¹, 余珊珊², 曹瑾¹, 张天竺¹, 吴东凯¹, 倪逸珂¹, 左从林^1#, 胡晓敏^2,*

¹昭衍（苏州）新药研究中心有限公司, 江苏苏州 215421;
²国家药品监督管理局药品审评中心,北京 100022

收稿日期:2020-05-09 出版日期:2021-06-15 发布日期:2021-07-02
通讯作者: ^*胡晓敏,女,研究员,药品有效性与安全性评价。E-mail:huxm@cde.org.cn;^#为共同通信作者。
作者简介:张海飞,男,副研究员,新药非临床评价研究。
基金资助:
重大新药创制国家科技重大专项2018年度(2018ZX09201017-007)

Features and Requirements of Non-clinical Toxic Evaluation of Inhalable Drugs

ZHANG Haifei¹, YU Shanshan², CAO Jin¹, ZHANG Tianzhu¹, WU Dongkai¹, NI Yike¹, ZUO Conglin^1#, HU Xiaomin^2,*

¹Joinn labories, Inc. Taichang, Suzhou Jiangsu 215421, China;
²Center for Drug Evaluation, National Medical Products Administration, Beijing 100022, China

Received:2020-05-09 Online:2021-06-15 Published:2021-07-02

摘要/Abstract

摘要： 目的分析吸入药物非临床评价的特点与要求,为吸入新药开发提供参考。方法比较吸入途径给药与常规给药方式的特殊性,如吸入给药剂量计算、气溶胶发生、吸入给药系统可靠性、试验结果评价等,分析影响吸入药物非临床研究结果的因素,以进行合理设计、规范实施、科学分析非临床实验。结果吸入药物的递送剂量由计算而得,但需要在此基础上估算沉积剂量;在吸入给药过程中需要对环境参数进行密切监测;吸入毒理实验的结果分析方面,啮齿类动物由于解剖及生理结构特点,上呼吸道易于产生炎症;对吸入给药在肺部引起的巨噬细胞聚集需要谨慎分析;吸入生物药在肺部的主要反应为炎症反应。结论吸入药物存在药学特性及模型动物呼吸系统生理病理方面的特殊性,对非临床评价提出了特殊要求。

关键词: 吸入给药, 毒理, 非临床, 粒径, 气溶胶, 药物

Abstract: Objective To analyze the features and requirements of non-clinical evaluation of inhalable drugs in order to provide reference for development of new inhalable drugs. Methods The characteristics of inhalable drugs were analyzed, such as generation of aerosols, dosimetry, reliability of the inhalation system, and interpretation of results. Factors that affected the non-clinical evaluation of inhalable drugs were identified so as to help design, conduct and analyze non-clinical experiments. Results The delivered dose of inhalable drugs was calculated, on the basis of which the deposited dose was estimated. During inhalation, the environmental parameters had to be monitored intensively. Inflammation in the upper airway was frequently noted due to the physiological and anatomical features of rodents. Aggregations of macrophages in the lung required cautious analysis. For inhalable biological drugs, the most common adverse reaction was inflammation. Conclusion The pharmaceutical properties of inhalable drugs place special demands on non-clinical evaluation.

Key words: inhalation, toxicity, non-clinical, particle size, aerosols, drugs

中图分类号:

R965.3

张海飞, 余珊珊, 曹瑾, 张天竺, 吴东凯, 倪逸珂, 左从林, 胡晓敏. 吸入药物非临床毒性评价特点与要求[J]. 中国药物警戒, 2021, 18(6): 570-574.

ZHANG Haifei, YU Shanshan, CAO Jin, ZHANG Tianzhu, WU Dongkai, NI Yike, ZUO Conglin, HU Xiaomin. Features and Requirements of Non-clinical Toxic Evaluation of Inhalable Drugs[J]. Chinese Journal of Pharmacovigilance, 2021, 18(6): 570-574.

参考文献

[1] Leach, CL.Inhalation aspects of therapeutic aerosols[J]. Toxicologic Pathology, 2007, 35: 23-26.
[2] Issar M, Mobley C, Khan P, et al.Pharmacokinetics and pharma-codynamics of drug delivery to the lungs[M]. 2nd ed. Pharmaceutical Inhalation Aerosol Technology, 2004: 198-233.
[3] Driscoll KE, Costa DL, Hatch G, et al.Intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: uses and limitations[J]. Toxicology Sciences, 2000, 55: 24-35.
[4] OECD. Guidance document on acute inhalation toxicity testing.environmental health and safety monograph series on testing and assessment [R]. No. 39, 2009.
[5] Raabe OG, Al-Bayati MA, Teague SV, et al.Regional deposition of inhaled monodisperse coarse and fine aerosol particles in small laboratory animals[J]. The Annals of Occupational Hygiene, 1988, 32: 53-63.
[6] Alexander DJ, Collins CJ, Derek WC.et al.Association of inhalation toxicologists (AIT)working party recommendation for standard delivered dose calculation and expression in nonclinical aerosol inhalation toxicology studies with pharmaceuticals[J]. Inhalation Toxicology, 2008, 20: 1179-1189.
[7] OECD Guideline for the testing of chemicals Subacute Inhalation Toxicity: 28-Day Study[R]. No. 412, 2018.
[8] Snipes MB.Long-term retention and clearance of particles inhaled by mammalian species[J]. Critical Reviews in Toxicology, 1989, 20: 175-211.
[9] Bennett JA, Harrison TW, Tattersfield AE.The contribution of the swallowed fraction of an inhaled dose of salmeterol to it systemic effects[J]. European Respiratory Society, 1999, 13: 445-448.
[10] Joseph J, Chang HA, Andrews PA, et al.Considerations for toxicology studies of respiratory drug products[J]. Regulatory Toxicology and Pharmacology, 1997, 25: 189-193.
[11] Birgit K, Christine R, Gerd Morawietz, et al, Revised guides for organ sampling and trimming in rats and mice[J]. Experimental and Toxicologic Pathology, 2004, 55(6): 413-431.
[12] Lewis DJ.Morphological assessment of pathological changes within the rat larynx[J]. Toxicologic Pathology, 1991, 19: 352-357.
[13] Vasanthi M, Alexander DJ, Pilling AM.A comparison of rodent and nonrodent laryngeal and tracheal bifurcation sensitivities in inhalation toxicity studies and their relevance for human exposure[J]. Toxicologic Pathology, 2017, 45(1): 216-222.
[14] Renne RA, Sagartz JW, Burger GT.Interspecies variations in the histology of toxicologically important areas in the larynges of CRL: CD rats and Syrian golden hamsters[J]. Toxicologic Pathology ,1993, 35: 542-46.
[15] Renne RA, Gideon KM.Types and patterns of response in the larynx following inhalation[J]. Toxicologic Pathology, 2006, 34: 281-285.
[16] Sato J, Doi T, Wako Y, et al. Histopathology of incidental findings in Beagles used in toxicity studies[J]. Toxicologic Pathology, 2012, 25(1): 103-134.
[17] Martonen TB.Deposition patterns of cigarette smoke in human airways[J]. American Industrial Hygiene Association Journal, 1992, 53(1): 6-18.
[18] Oberdorster G, Oberdorster E, Oberdorster J.Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles[J]. Environmental Health Perspectives, 2005, 113(7): 823-839.
[19] Oberdorster G, Ferin J, Lehnert BE.Correlation between particle-size, in-vivo particle persistence, and lung injury[J]. Environmental Health Perspectives, 1994, 102: 173-179.
[20] Chamanza R, Marxfeld HA, Blanco, AI.et al.Incidences and range of spontaneous findings in control cynomolgus monkeys (Macaca fascicularis) used in toxicity studies[J]. Toxicol-ogic Pathology, 2010, 38: 642-657.
[21] Jones RM, Neef N.Interpretation and prediction of inhaled drug particle accumulation in the lung and its associated toxicity[J]. Xenobiotica, 2012, 42(1): 86-93.
[22] Lewis DJ. Mckevitt TP.Respiratory system[C]. P.J.A. SAHOTA P, Toxicological Patho-logy: Non-Clinical Safety Assessment. CRC Press, 2013: 367-420.
[23] Bermudez E. Mangum JB. Asgharian B, et al.Long-term pulmonary responses of three laboratory rodent species to subchronic inhalation of pigmentary titanium dioxide particles[J]. Toxicological Sciences, 2002, 70(1): 86-97.
[24] International Life Sciences Institute (ILSI). The relevance of the rat lung response to particle overload for human risk assessment: a workshop consensus report[R]. Inhalation Toxicology, 2000, 12(1-2): 1-17.
[25] Matucci A, Nencini F, Maggi E, et al.Hypersensitivity reactions tobiologics used in rheumatology[J]. Expert Review Clinical Immunology, 2019, 15(12): 1263-1271.
[26] Bodier ME, Respaud R, Perret G, et al.Protein stability during nebulization: mind the collection step![J]. European Journal of Pharmaceutics and Biopharmaceutics, 2020, 152: 23-34.
[27] Wolff RK.Safety of inhaled proteins for therapeutic use[J]. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 1998, 11(4): 197-219.
[28] Ning JK, Pang SQ.Analysis of the utilization of oxygen atomization inhalation given to inpatients of our hospital[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2018, 15(5): 304-307.

吸入药物非临床毒性评价特点与要求

Features and Requirements of Non-clinical Toxic Evaluation of Inhalable Drugs

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

[1]	郭宁子, 刘丽, 岳瑞齐, 冯慧庆, 杨化新, 魏宁漪, 陈华. 激光衍射法测定西格列他钠粒径分布[J]. 中国药物警戒, 2024, 21(2): 147-151.
[2]	李嘉昕, 刘慧敏, 钱文秀, 马宁, 宋丽丽, 李遇伯. 基于中药系统毒理学数据库的中药致肾毒性及药物规律研究[J]. 中国药物警戒, 2024, 21(2): 173-180.
[3]	徐伟佳, 彭崎, 黄海渝, 张磊姣, 肖华, 吴雪. 285例新型抗肿瘤药物不良反应分析[J]. 中国药物警戒, 2024, 21(2): 199-203.
[4]	陈玉艳, 张明霞, 张涛, 张晋. 斯鲁利单抗注射液致间质性肺炎不良反应1例分析[J]. 中国药物警戒, 2024, 21(2): 213-215.
[5]	靳生菊, 周苗, 张佳宁, 葛宫慧, 张廷剑, 孟繁浩. 新型黄嘌呤氧化酶抑制剂对痛风治疗的研究进展[J]. 中国药物警戒, 2024, 21(2): 223-228.
[6]	王欣, 史磊磊, 张雨涵, 谢允东, 刘继平. 多药耐药相关蛋白转运体在药物性肝损伤中的作用研究进展[J]. 中国药物警戒, 2024, 21(2): 229-234.
[7]	柏兆方, 湛小燕, 姚清, 陈思敏, 赵旭, 肖小河. 中药安全性评价理论创新与技术突破：病证毒理学[J]. 中国药物警戒, 2024, 21(1): 6-14.
[8]	高源, 石伟, 肖小河, 柏兆方, 王伽伯. 特异质型药物性肝损伤体内评价模型研究进展[J]. 中国药物警戒, 2024, 21(1): 33-39.
[9]	刘敏, 陈艳, 刘文东, 王海学. 药物临床试验期间安全性数据快速报告的更新与思考[J]. 中国药物警戒, 2024, 21(1): 98-101.
[10]	陈华炎, 江东波, 郭春连, 杨家琪, 黎雨欣, 蔡伟明. 326例奈玛特韦片/利托那韦片治疗新型冠状病毒感染安全性分析[J]. 中国药物警戒, 2024, 21(1): 107-110.
[11]	高旭, 彭金娥, 李兴旺, 张伟. 猴痘抗病毒药物及疫苗研究现状[J]. 中国药物警戒, 2024, 21(1): 111-116.
[12]	詹姆斯·布坎南. 用 nR 改良海氏法则及 P_ALT 评估药物性肝损伤研究进展[J]. 中国药物警戒, 2024, 21(1): 117-120.
[13]	马瑞泽, 陈志海. 抗新型冠状病毒的小分子药物最新研究进展[J]. 中国药物警戒, 2023, 20(9): 961-966.
[14]	夏旭东, 黎美霞, 孙阳, 杨胜亚. 药品上市许可持有人药物警戒远程检查流程探讨[J]. 中国药物警戒, 2023, 20(9): 967-970.
[15]	里筱竹, 王蔷, 逄瑜, 张轶菁. 个例药品不良反应报告管理浅析与思考[J]. 中国药物警戒, 2023, 20(9): 975-977.