Ph2a Study: Rifampin, Merrem, Augmentin for Tuberculosis IND 129159; 12/31/2015

Ph2a 研究：利福平、Merrem、Augmentin 治疗结核病 IND 129159；

• 批准号: 10014610
• 负责人: Kelly E. Dooley
• 金额: $ 50万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10014610
• 关键词: Ph2a; Study; Rifampin; Merrem; Augmentin

Project Summary/Abstract Tuberculosis (TB) is the single greatest infectious disease killer globally. Multidrug-resistant (MDR) TB, caused by M. tuberculosis resistant to isoniazid and rifampin, threatens global TB control. The lengthy, expensive treatments that can cure MDR-TB are often not accessible by patients who need them, are only 50% successful, and cause unacceptably high toxicity. Rifampin, by virtue of its sterilizing activity against M. tuberculosis, plays an indispensable role in modern six-month `short-course' therapy for drug-susceptible TB. In MDR-TB, it is the infecting bacteria's resistance to rifampin that is primarily responsible for the prolonged treatment duration of 18-24 months that is required when rifampin cannot be used. Up to now, there are simply no anti-TB drugs with demonstrated sterilizing potency equivalent to that of rifampin. Strategies that restore rifampin activity, even partially, may have important treatment shortening effects for MDR-TB. Strategies to potentiate rifampin activity -- that is, to increase the antituberculosis effect of a given dose of rifampin -- may also be relevant for treatment of drug-susceptible TB. Lamichhane and colleagues at Johns Hopkins University recently showed that the combination of rifampin plus a carbapenem/β- lactamase inhibitor is synergistic and lowers the effective rifampin MIC, even restoring the activity of rifampin in vitro against rifampin-resistant M. tuberculosis. Further, the combination of meropenem plus amoxicillin/clavulanate has potent antituberculosis activity in human TB and is safe and well-tolerated. We propose a focused, proof-of-concept clinical trial to determine whether, in pulmonary TB patients, a carbapenem/ β-lactamase inhibitor combination can serve as a rifampin `sensitizer' and thereby potentiate the antituberculosis activity of rifampin. In this phase 2a randomized, open-label trial we will enroll patients with rifampin-susceptible pulmonary TB as well as patients with rifampin-resistant pulmonary TB. Participants will be randomized to receive one of 5 treatments for 7 days: Baseline DST Regimen Regimen Components Rifampin resistant Randomized (1:1) to: A Rifampin Meropenem Amx/Clv B - Meropenem Amx/Clv Rifampin susceptible Randomized (1:1:1) to: C Rifampin Meropenem Amx/Clv D - Meropenem Amx/Clv E Rifampin - - Abbreviations: DST, drug-susceptibility testing; Amx/Clv, amoxicillin/clavulanate The primary endpoint is mean daily fall in log10 colony forming units of M. tuberculosis per mL of sputum over 7 days of treatment. Safety of the regimens will be assessed. We will incorporate intensive pharmacokinetic (PK) and mycobacteriology assessments which, in the context of a range of M. tuberculosis minimum inhibitor concentrations (MICs) and expected inter-individual rifampin PK variability, will allow determination of the pharmacodynamic relationships between rifampin, rifampin area under the concentration-time curve (AUC), and antituberculosis activity when rifampin is administered in combination with meropenem and amoxicillin/clavulanate. The ability to recoup rifampin's antituberculosis activity, even partially, through combination with a carbapenem and β-lactamase inhibitor would transform the treatment of MDR-TB and have implications for individual patients and public health. Potentiation of rifampin activity is also likely to be relevant for treatment of drug-susceptible TB, not only in certain patient sub-groups but also as a component of a treatment-shortening strategy applicable to the majority of TB patients worldwide.

项目概要/摘要 结核病 (TB) 是全球最大的传染病杀手。耐多药（MDR）结核病， 由耐异烟肼和利福平的结核分枝杆菌引起，威胁着全球结核病控制。冗长的、 需要治疗的患者往往无法获得能够治愈耐多药结核病的昂贵治疗方法，只能 50% 成功，并导致令人无法接受的高毒性。利福平凭借其杀菌活性 结核分枝杆菌在现代药物敏感性六个月“短期”治疗中发挥着不可或缺的作用 结核病。在耐多药结核病中，感染细菌对利福平的耐药性是造成耐药性结核病的主要原因。 当不能使用利福平时，需要延长治疗时间 18-24 个月。到目前为止， 根本没有任何抗结核药物具有与利福平同等的杀菌效力。 恢复利福平活性的策略，即使是部分恢复，也可能对缩短治疗时间产生重要影响。 耐多药结核病。增强利福平活性的策略——即增加给定药物的抗结核作用 利福平的剂量——也可能与药物敏感结核病的治疗有关。拉米查恩和同事 约翰霍普金斯大学最近表明，利福平加碳青霉烯/β- 内酰胺酶抑制剂具有协同作用，降低利福平的有效 MIC，甚至恢复利福平的活性 利福平在体外对抗利福平耐药结核分枝杆菌。进一步地，美罗培南加美罗培南的组合 阿莫西林/克拉维酸对人类结核病具有有效的抗结核活性，并且安全且耐受性良好。 我们提出了一项有针对性的概念验证临床试验，以确定肺结核患者中是否存在 碳青霉烯/β-内酰胺酶抑制剂组合可以作为利福平“增敏剂”，从而增强 利福平的抗结核活性。在这个 2a 期随机、开放标签试验中，我们将招募患者 对利福平敏感的肺结核以及对利福平耐药的肺结核患者。 参与者将随机接受 5 种治疗中的一种，为期 7 天： 基线 DST 方案 方案组成部分 利福平 抵抗的 随机化 (1:1) 至：利福平美罗培南 Amx/Clv B - 美罗培南 Amx/Clv 利福平 易受影响的 随机化 (1:1:1) 至：C 利福平 美罗培南 Amx/Clv D - 美罗培南 Amx/Clv E 利福平 - - 缩写：DST，药敏试验； Amx/Clv，阿莫西林/克拉维酸 主要终点是每毫升痰中结核分枝杆菌菌落形成单位的平均每日下降量 治疗时间超过7天。将评估治疗方案的安全性。我们将结合密集 药代动力学（PK）和分枝杆菌学评估，在一系列分枝杆菌的背景下。 结核病最低抑制剂浓度 (MIC) 和预期的个体间利福平 PK 变异性， 将允许确定利福平、利福平面积之间的药效关系 利福平联合用药时的浓度-时间曲线（AUC）和抗结核活性 与美罗培南和阿莫西林/克拉维酸一起使用。 通过与利福平联合使用，能够恢复利福平的抗结核活性，甚至部分恢复 碳青霉烯类和β-内酰胺酶抑制剂将改变耐多药结核病的治疗方法，并对 个体患者和公共卫生。利福平活性的增强也可能与 药物敏感结核病的治疗，不仅针对某些患者亚组，而且作为治疗方案的一个组成部分 适用于全球大多数结核病患者的缩短治疗策略。

项目成果

A treatment recommender clinical decision support system for personalized medicine: method development and proof-of-concept for drug resistant tuberculosis.

• DOI: 10.1186/s12911-022-01790-0
• 发表时间: 2022-03-02
• 期刊: BMC medical informatics and decision making
• 影响因子: 3.5
• 作者: Verboven L;Calders T;Callens S;Black J;Maartens G;Dooley KE;Potgieter S;Warren RM;Laukens K;Van Rie A
• 通讯作者: Van Rie A

The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis.

• DOI: 10.3389/fphar.2021.637618
• 发表时间: 2021
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Abulfathi AA;de Jager V;van Brakel E;Reuter H;Gupte N;Vanker N;Barnes GL;Nuermberger E;Dorman SE;Diacon AH;Dooley KE;Svensson EM
• 通讯作者: Svensson EM