模型引导的药物开发在新药研发中的应用

doi:10.12092/j.issn.1009-2501.2020.01.001

摘要/Abstract

摘要： 模型引导的药物开发（MIDD）通过应用各类数学模型进行定量分析，从而指导新药开发和决策。MIDD在先进药物研发企业中的研发决策应用，以及先进监管部门的监管决策尤其美国FDA的应用，已较为普遍和成熟，但在国内创新药研究中的普及率还相对较低。本文根据作者实际工作经验，基于当前新药临床药理专业审评中常见的模型研究内容和有代表性的案例，结合国内外MIDD相关技术指导原则，对MIDD的主要应用范畴进行了探讨，并简要讨论了MIDD应用于新药研发的几点建议和注册申报的一般考虑，供新药开发企业和研究者讨论或参考。

关键词: 新药, 模型引导的药物开发, 量效关系, 剂量优化, 群体药代动力学, 药代动力学/药效动力学

Abstract: Model-informed drug development (MIDD) refers to the application of various mathematical models in drug development, in order to facilitate the decision-making process. There have been common and mature applications of MIDD to address drug development and regulatory questions in interactional industries and advanced regulatory agencies, especially the US FDA. However, its application in innovative drug development is relatively rare in China. Representative case studies, clinical pharmacology review ex-periences, and relevant guidelines are reviewed in this article to present a preliminary discussion on the main applications of MIDD. Additionally, several suggestions for the application of MIDD in new drug development as well as general considerations for new drug registration are proposed in this paper, for the discussion or reference of industries and researchers.

Key words: new drug, model-informed drug development (MIDD), exposure-response relationship, dose optimization, population pharmacokinetics, pharmacokinetics/pharmacodynamics (PK/PD)

中图分类号:

R969

李健，杨进波，王玉珠. 模型引导的药物开发在新药研发中的应用[J]. 中国临床药理学与治疗学, 2020, 25(1): 1-8.

LI Jian, YANG Jinbo, WANG Yuzhu. Applications of model-informed drug development (MIDD) on new drug research and development[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2020, 25(1): 1-8.

参考文献

［1］王玉珠, 杨进波. 定量药理学在确定非劣效试验界值中的作用［J］.中国临床药理学杂志, 2017, 33(23): 2515-2520.
［2］尹芳, 王玉珠, 郑青山. 茚达特罗上市剂量选择的论战:美国FDA定量药理学审评的故事［J］.中国临床药理学与治疗学, 2018, 23(9): 1031-1039.
［3］陈文君, 周田彦, 卢炜. 群体药物动力学及其在新药研究中的应用［J］. 药学学报, 2017, 52(3): 371-377.
［4］Li J, Chen R, Yao QY, et al. Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model［J］. Acta Pharmacol Sin, 2018, 39(3): 472-481.
［5］Yao QY, Li J, Chen R, et al. Preclinical PK/PD model for the combinatorial use of dexamethasone and sulpiride in the treatment of breast cancer［J］. Acta Pharmacol Sin, 2019, 40(12), 1596-1602.
［6］ (原)国家食品药品监督管理总局. 儿科人群药代动力学研究技术指导原则［EB/OL］. 北京: (原)国家食品药品监督管理总局,（2014-07-11）［2019-08-22］. http://www.nmpa.gov.cn/WS04/CL2196/324067.html.
［7］U.S. Food & Drug Administration (FDA). Guidance for Industry-Population Pharmacokinetics ［EB/OL］. Maryland (USA): FDA, （2019-07-11）［2019-08-22］. https://www.fda.gov/media/128793/download.
［8］European Medicines Agency (EMA). Guideline on similar biological medicinal products containing monoclonal antibodies-non-clinical and clinical issues［EB/OL］. Amsterdam (Netherlands): EMA, （2012-05-01）［2019-12-02］ . https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-containing-monoclonal-antibodies-non-clinical_en.pdf.
［9］李健, 闫方, 高丽丽, 等. 单克隆抗体生物类似药药代动力学比对研究的剂量选择一般考虑［J］. 中国临床药理学杂志, 2019, 35(15): 1716-1720.
［10］国家药品监督管理局药品审评中心. 接受药品境外临床试验数据的技术指导原则［EB/OL］. 北京: 国家药品监督管理局药品审评中心,（2018-07-11）［2019-12-02］. http://www.cde.org.cn/zdyz.do?method=largePage&id=308.
［11］The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Ethnic factors in the acceptability of foreign clinical data ［EB/OL］. Geneva (Switzerland): ICH, （1998-02-05）［2019-12-02］ . https://database.ich.org/sites/default/files/E5_R1_Guideline.pdf.
［12］The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). General principles for planning and design of Muti-Regional Clinical Trials［EB/OL］. Geneva (Switzerland): ICH, （2017-11-16）［2019-12-02］ . https://database.ich.org/sites/default/files/E17EWG_Step4_2017_1116.pdf.
［13］Zhang J, Cai JL, Bello A, et al. Model-based population pharmacokinetic analysis of Nivolumab in Chinese patients with previously treated advanced solid tumors, including Non-small cell lung cancer ［J］. J Clin Pharmacol, 2019, 59(10): 1415-1424.
［14］国家药品监督管理局药品审评中心. 肝功能损害患者的药代动力学研究技术指导原则［EB/OL］. 北京: 国家药品监督管理局药品审评中心,（2012-05-15）［2019-08-22］ . http://www.cde.org.cn/zdyz.do?method=largePage&id=150.
［15］国家药品监督管理局药品审评中心. 肾功能损害患者的药代动力学研究技术指导原则［EB/OL］. 北京: 国家药品监督管理局药品审评中心,（2012-05-15）［2019-08-22］. http://www.cde.org.cn/zdyz.do?method=largePage&id=145.
［16］The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Studies in support of special population: Geriatrics ［EB/OL］. Geneva (Switzerland): ICH, （1993-06-24）［2019-12-02］ . https://database.ich.org/sites/default/files/E7_Guideline.pdf.
［17］Sabina P, Elliot O, Nita I, et al. Update and trends on pharmacokinetic studies in patiens with impaired renal function: practical insight into application of the FDA and EMA guidelines ［J］. Exp Rev Clinl Pharmacol, 2017, 10(3): 273-283.
［18］U.S. Food & Drug Administration (FDA). Guidance for Industry-Clinical Drug Interaction Studies-Study Design, Data Analysis, and Clinical Implications ［EB/OL］. Maryland (USA): FDA, （2017-10-25）［2019-12-02］. https://www.fda.gov/media/82734/download.
［19］马广立, 许玲, 陈锐, 等. 新药研发中群体药动学/药效学研究的一般考虑［J］. 中国临床药理学与治疗学, 2019, 24(11): 1201-1220.
［20］Wang Y, Zhu H, Madabushi R, et al. Model-informed drug development: current US regulatory practice and future considerations ［J］. Clin Pharmacol Ther, 2019, 105(4): 899-911.
［21］Bi YW, Liu J, Wang J, et al. Model-informed drug development approach supporting approval of adalimumab (HUMIRA) in adolescent patients with hidradenitis suppurativa: a regulatory perspective ［J］. AAPS J, 2019, 21(5): 91.
［22］Bi Y, Liu J, Furmanski B, et al. Model-informed drug development approach supporting approval of the 4-week (Q4W) dosing schedule for nivolumab (Opdivo) across multiple indications: a regulatory perspective ［J］. Ann Oncol, 2019, 30(4): 644-651.
［23］Wang Y, Bhattaram AV, Jadhav PR, et al. Leveraging prior quantitative knowledge to guide drug development decisions and regulatory science recommendations: impact of FDA pharmacometrics during 2004-2006 ［J］. J Clin Pharmacol, 2008, 48(2): 146-156.
［24］Woosley RL. They are from the government and they really are here to help you ［J］. J Clin Pharmacol, 2008, 48(2): 142-143.
［25］Stanski DR, Orloff JJ. Communicating with the FDA: The "Third rail" of a new model for drug development ［J］. J Clinl Pharmacol, 2008, 48(2): 144-145.
［26］U.S. Food & Drug Administration (FDA). Guidance for Industry-End-of-Phase 2A Meetings ［EB/OL］. Maryland (USA): FDA, （2009-09-18）［2019-12-02］. https://www.fda.gov/media/72211/download.
［27］(原)国家食品药品监督管理总局. 药物临床试验的一般考虑指导原则［EB/OL］. 北京: (原)国家食品药品监督管理总局,(2017-01-18)［2019-08-22］.http://www.nmpa.gov.cn/WS04/CL2138/300278.html.
［28］(原)国家食品药品监督管理总局. 抗菌药物药代动力学/药效学研究技术指导原则［EB/OL］. 北京: (原)国家食品药品监督管理总局,(2017-08-04)［2019-08-22］. http://www.nmpa.gov.cn/WS04/CL2138/300379.html.
［29］国家药品监督管理局药品审评中心. 药物相互作用研究指导原则［EB/OL］. 北京: 国家药品监督管理局药品审评中心,(2012-05-15)［2019-08-22］. http://www.cde.org.cn/zdyz.do?method=largePage&id=147.
［30］国家药品监督管理局药品审评中心. 化学药物临床药代动力学研究技术指导原则［EB/OL］. 北京: 国家药品监督管理局药品审评中心,(2005-03-01)［2019-08-22］. http://www.cde.org.cn/zdyz.do?method=largePage&id=2070.
［31］European Medicines Agency (EMA). Guideline on reporting the results of population pharmacokinetic analyses ［EB/OL］. Amsterdam (Netherlands): EMA, (2007-06-21)［2019-08-22］. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-reporting-results-population-pharmacokinetic-analyses_en.pdf.
［32］U.S. Food & Drug Administration (FDA). Guidance for Industry-Physiologically Based Pharmacokinetic Analyses-Format and Content ［EB/OL］. Maryland (USA): FDA, (2018-09-04)［2019-12-02］. https://www.fda.gov/media/101469/download.
［33］European Medicines Agency (EMA). Guideline on the reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation ［EB/OL］. Amsterdam (Netherlands): EMA, (2018-12-13)［2019-12-02］.https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-reporting-physiologically-based-pharmacokinetic-pbpk-modelling-simulation_en.pdf.
［34］The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Minutes of MC meeting Geneva ［EB/OL］. Geneva (Switzerland): ICH, (2018-01-31)［2019-12-02］.https://admin.ich.org/sites/default/files/2019-05/MC_Minutes_ICH_Meeting_Geneva_Nov2017%20%281%29.pdf.
［35］The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Minutes of MC meeting Amsterdam ［EB/OL］. Geneva (Switzerland): ICH, (2018-08-09)［2019-12-02］.https://admin.ich.org/sites/default/files/2019-08/ICH38_MC_Minutes_Meeting_Final_2019_0724_public.pdf.
［36］U.S. Food & Drug Administration (FDA). Guidance for Industry - General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products ［EB/OL］. Maryland (USA): FDA, (2014-12-08)［2019-12-02］. https://www.fda.gov/media/90358/download.
［37］European Medicines Agency (EMA). Guideline on the use of pharmacokinetics and pharmacodynamics in the development of antimicrobial medicinal products ［EB/OL］. Amsterdam (Netherlands): EMA, (2016-07-21)［2019-12-02］.https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-use-pharmacokinetics-pharmacodynamics-development-antimicrobial-medicinal-products_en.pdf.
［38］The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Dose-response information to support drug registration ［EB/OL］. Geneva (Switzerland): ICH, (1994-03-10)［2019-12-02］. https://database.ich.org/sites/default/files/E4_Guideline.pdf.

[1]	李梦雪, 何杰, 余霞霞, 胡琳璘, 邵华. 利妥昔单抗群体药代动力学研究进展[J]. 中国临床药理学与治疗学, 2023, 28(4): 468-474.
[2]	马广立, 张菁. 定量药理学在疫苗研发中应用的概述与展望[J]. 中国临床药理学与治疗学, 2023, 28(3): 315-322.
[3]	徐涛, 朱素燕, 邱相君, 徐萍. 肾功能不全患者人群中替考拉宁群体药代动力学模型的建立与验证[J]. 中国临床药理学与治疗学, 2022, 27(9): 977-983.
[4]	林良沫, 符祥俊, 钟莉莉, 王和芳, 吴琼诗, 肖坚. 中性粒细胞缺乏患者万古霉素群体药代动力学模型的建立[J]. 中国临床药理学与治疗学, 2021, 26(9): 1014-1022.
[5]	刘璐, 陈笑艳. 国产小分子化学创新药临床药物相互作用研究现状[J]. 中国临床药理学与治疗学, 2021, 26(8): 863-875.
[6]	郝海平. 我国代谢调控与药物靶标发现研究的进展与展望[J]. 中国临床药理学与治疗学, 2021, 26(8): 955-963.
[7]	徐国防, 张思森, 刘平, 梅家转, 刘玮玮, 刘亚欧, 齐琦. 卡培他滨在中国乳腺癌患者中的群体药代动力学研究[J]. 中国临床药理学与治疗学, 2021, 26(5): 552-559.
[8]	施樱子, 赵杨. 中美药品监管激励政策对我国创新药国内外同步开发的影响——基于泽布替尼的实证研究[J]. 中国临床药理学与治疗学, 2021, 26(5): 560-569.
[9]	李文超, 白向荣, 李晓玲, 姜德春. 替加环素在治疗感染性疾病中的群体药代动力学/药效学研究进展[J]. 中国临床药理学与治疗学, 2021, 26(11): 1265-1272.
[10]	孙搏, 付淑军, 陈桂良, 李丽. 药物相互作用研究在新药研发和审评决策中的应用[J]. 中国临床药理学与治疗学, 2021, 26(10): 1095-1102.
[11]	张玉龙, 赵颖, 张伟. 药物微生物组在新药研发中的应用[J]. 中国临床药理学与治疗学, 2021, 26(1): 58-64.
[12]	郝玉奇, 肖遥, 王乾, 姜兴旭. 抗新型冠状病毒药物与治疗浅谈[J]. 中国临床药理学与治疗学, 2020, 25(6): 716-720.
[13]	李健, 杨进波, 王玉珠. 创新药群体药代动力学研究申报资料的探讨[J]. 中国临床药理学与治疗学, 2020, 25(5): 546-549.
[14]	李健，闫方，杨进波，王玉珠. 从纳武利尤单抗用法用量变更看模型引导的药物开发方法在剂量优化中的应用[J]. 中国临床药理学与治疗学, 2020, 25(4): 408-412.
[15]	陈文君，阮邹荣，相小强. 生理药代动力学模型的发展应用动态及其与其他建模方法的融合[J]. 中国临床药理学与治疗学, 2020, 25(3): 299-305.