The Hollow Fiber System Model in the Nonclinical Evaluation of Antituberculosis Drug Regimens
The Hollow Fiber System Model in the Nonclinical Evaluation of Antituberculosis Drug Regimens
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DOI：
10.1093/cid/civ460
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发表时间：
2015-08-15
影响因子：
11.8
通讯作者：
Toerner, Joseph G.
中科院分区：
文献类型：
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作者：
Chilukuri, Dakshina;McMaster, Owen;Toerner, Joseph G.
结核病仍然是一个严重的公共卫生挑战，全球活动性疾病的流行率估计为860万，死亡率为每年130万[1]。2012年，美国疾病控制和预防中心报告了大约10000例病例，其中约1%同时对利福平和异烟肼耐药[2]。这些流行病学数据强调了对新的抗结核药物的需求，包括新的作用机制、改善的安全性和更少的药物-药物相互作用。新的联合疗法在改善全球结核病的管理和控制方面将特别重要。有效和迅速地将新的抗结核药物和药物组合带入后期临床试验的途径是一个关键的公共卫生目标。在结核病药物治疗的最新进展中，缩短的治疗方案对公共卫生产生了巨大的影响。与20世纪中叶单一或双药治疗1年或更长时间的做法不同，今天对易感结核病患者的护理标准是6个月的2HRZE/4HR方案，包括2个月的异烟肼(H)、利福平(R)、吡津酰胺(Z)和乙胺丁醇(E)治疗，然后是4个月的异烟肼和利福平治疗。2HRZE/4HR方案主要是由英国医学研究理事会[3]在1970-1982年间通过许多早期阶段的2期临床试验开发的，其中研究了多种联合用药方案的变化。这一开发过程非常费力，突显了对工具的需求来为方案的开发提供信息，包括更有效地设计的后期第二阶段临床试验。在这份临床传染病补充资料中，来自结核病药物方案关键路径(CPTR)的作者和学术界提出了一个体外模型来评估抗结核分枝杆菌的药物活性；具体地说，作者假设结核的中空纤维系统模型(HFS-TB)可能被用来确定适合后期第二阶段临床试验的有希望的方案。HFS-TB可用于模拟抗分枝杆菌药物的许多药代动力学特征，并允许探索与临床环境中的结核病治疗潜在相关的浓度-效应关系。相比之下，这种关系的临床鉴定(即，在后期临床试验评估之前)可能需要几年时间。此外，HFS-TB可以通过重申微生物动力学(例如，杆菌亚群的休眠)来模拟耐药性的出现。中空纤维系统模型(HFS)在个体抗菌药物开发过程中的有效应用使研究人员能够预测药效学特性，从而更有效地确定临床试验的给药方案。例如，它被用来预测阿莫西林预防儿童和孕妇吸入性炭疽病的暴露和疗效[4]。与数学相一致
Tuberculosis remains a serious public health challenge, with the global prevalence of active disease estimated at 8.6 million and the mortality rate at 1.3 million deaths per year [1]. In 2012, the Centers for Disease Control and Prevention reported approximately 10 000 cases in the United States, of which approximately 1% were resistant to both rifampin and isoniazid [2]. These epidemiologic data highlight the need for new antituberculosis drugs, encompassing novel mechanisms of action, improved safety profiles, and fewer drug–drug interactions. New combination regimens will be of particular importance in improving the management and control of tuberculosis globally. A pathway for bringing new antituberculosis drugs and drug combinations efficiently and promptly into laterstage clinical trials is a critical public health goal. Among recent advances in drug therapy for tuberculosis, shortened treatment regimens have had a dramatic public health impact. Instead of the mid-20th-century practice of administering single-or dual-drug treatments for 1 year or longer, the standard of care today for patients with susceptible tuberculosis is the 6-month 2HRZE/4HR regimen, consisting of 2 months of treatment with isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E) followed by 4 months of isoniazid and rifampin. The 2HRZE/4HR regimen was developed, primarily by the British Medical Research Council [3], during 1970–1982, through many earlystage phase 2 clinical trials, in which multiple variations of combination drug regimens were investigated. This development process was highly laborious, underscoring the need for tools to inform regimen development, including more efficiently designed, later-stage phase 2 clinical trials.In this supplement of Clinical Infectious Diseases, authors from the Critical Path to TB Drug Regimens (CPTR) and academia present an in vitro model to evaluate drug activity against Mycobacterium tuberculosis; specifically, the authors posit that the hollow fiber system model of tuberculosis (HFS-TB) might be used to identify promising regimens appropriate for testing in laterstage phase 2 clinical trials. The HFS-TB can be used to simulate many pharmacokinetic characteristics of antimycobacterial drugs and allows for the exploration of concentration–effect relationships potentially relevant to the treatment of tuberculosis in the clinical setting. In contrast, the clinical identification of such relationships (ie, prior to later-stage clinical trial evaluations) may take several years. In addition, the HFS-TB can model the emergence of resistance by reiterating microbial dynamics (eg, dormancy of bacilli subpopulations). The effective use of the hollowfiber system model (HFS) in the course of developing individual antibacterial drugs has allowed investigators to predict pharmacodynamic characteristics and thereby determine dosing regimens for clinical trials more efficiently. For example, it was used to predict exposure and efficacy of amoxicillin for the prophylaxis of inhalational anthrax in children and pregnant women [4]. In concert with mathematic