Safety, pharmacokinetics, and resistance to bedaquiline in XDR TB and HIV

广泛耐药结核病和艾滋病毒中贝达喹啉的安全性、药代动力学和耐药性

• 批准号: 8923027
• 负责人: James C M Brust
• 金额: $ 46.35万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-05 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8923027
• 关键词: Advisory Committees; African; Anti-Retroviral Agents; Area; Arrhythmia; CYP3A4 gene; Cardiac; Cessation of life; Clinical; Clinical Trials; Code; Cohort Studies; Data; Dose; Drug Interactions; Drug Kinetics; Drug Targeting; Drug resistance; Drug resistance in tuberculosis; Electrocardiogram; Enrollment; Epidemic; Extreme drug resistant tuberculosis; Fluoroquinolones; Genes; Genetic; Genetic Polymorphism; Guidelines; HIV; HIV drug resistance; Health; Immunosuppression; Individual; Lead; Life; Lopinavir/Ritonavir; Methods; Molecular; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mutation; Mycobacterium tuberculosis; Nevirapine; Operon; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Property; Public Health; Regimen; Research Priority; Resistance; Resistance development; Risk; Safety; Sampling; South Africa; Survival Rate; Torsades de Pointes; Toxic effect; Treatment Protocols; Tuberculosis; United States National Institutes of Health; antiretroviral therapy; base; clinical care; clinically significant; co-infection; cohort; efflux pump; genome sequencing; healthy volunteer; improved; inhibitor/antagonist; millisecond; mortality; novel; novel marker; patient population; prospective; public health relevance; resistance mechanism; success; treatment program; tuberculosis drugs; tuberculosis treatment

 DESCRIPTION (provided by applicant): Extensively drug-resistant tuberculosis (XDR TB) has emerged as a significant global epidemic and poses a particular threat to HIV-infected individuals. With few effective drugs available for treatment, XDR TB carries an extremely high mortality. Bedaquiline is the first new TB drug to receive FDA approval in 40 years and has shown considerable promise in early clinical trials of MDR TB. The drug has not, however, been well-studied in patients with XDR TB or in those with HIV co-infection who are receiving antiretroviral therapy (ART). As a result, much remains unknown about the mechanisms of resistance to this potentially transformative drug, the potential drug-drug interactions with common antiretroviral medications, and its safety in XDR TB or HIV. South Africa has among the highest burden of HIV and TB in the world, including a rapidly expanding epidemic of drug-resistant TB and HIV co-infection. In 2013, the National Department of Health created a treatment program to make bedaquiline available to patients with XDR and pre-XDR TB in combination with an optimized background regimen. The collision of XDR TB and HIV in South Africa offers a unique opportunity to study bedaquiline in patients who could benefit substantially from it, yet who have been largely excluded from the clinical trials. In Aim 1, we propose a prospective cohort study of XDR and pre-XDR TB participants to identify the genetic mechanisms of resistance to bedaquiline. Among participants who develop resistance, we will conduct whole genome sequencing of M. tuberculosis isolates to identify genetic polymorphisms associated with resistance. In Aim 2, we will examine drug-drug interactions of bedaquiline with ART. Bedaquiline is recommended to be given with either nevirapine or lopinavir/ritonavir-based regimens, based on small, single- dose studies in healthy volunteers. We will conduct intensive and sparse pharmacokinetic sampling on participants receiving bedaquiline, with or without ART. In Aim 3, we will determine the safety of administering bedaquiline with other QT-prolonging TB medications. We hypothesize that the co-administration of bedaquiline with clofazimine or fluoroquinolones will lead to additive increases in the QT interval and may lead to life-threatening QT prolongation requiring discontinuation of one or more of these medications. Each aim of this study will answer a fundamental question about bedaquiline that will directly inform its use in South Africa and globally. Our study will draw from the largest non-trial cohort of patients receiving bedaquiline anywhere in the world. The NIH and the Federal TB Task Force have identified specific priority research areas for the interaction between HIV and drug-resistant TB. This application will focus on two such areas for bedaquiline-new markers of resistance and pharmacologic interactions with ART-in South Africa, the epicenter of the convergent epidemics of drug-resistant TB and HIV.

 描述(由申请人提供)：广泛耐药结核病(XDR TB)已成为一种重大的全球流行病，并对艾滋病毒感染者构成特别威胁。由于几乎没有有效的治疗药物，广泛耐药结核病的死亡率极高。贝达奎林是40年来第一个获得FDA批准的结核病新药，在耐多药结核病的早期临床试验中显示出相当大的前景。然而，该药物在接受抗逆转录病毒治疗(ART)的广泛耐药结核病患者或艾滋病毒合并感染患者中尚未得到很好的研究。因此，对这种潜在变革性药物的耐药性机制、与常见抗逆转录病毒药物的潜在药物相互作用以及其在广泛耐药结核病或艾滋病毒中的安全性仍有许多未知之处。南非是世界上艾滋病毒和结核病负担最重的国家之一，包括耐药结核病和艾滋病毒混合感染的疫情迅速扩大。2013年，美国国家卫生部制定了一项治疗计划，将贝达奎兰与优化的背景方案相结合，为广泛耐药和广泛耐药前结核病患者提供贝达奎兰。南非广泛耐药结核病和艾滋病毒的碰撞提供了一个独特的机会来研究贝达奎兰在患者中的应用，这些患者可能会大大受益 然而，这些人基本上被排除在临床试验之外。在目标1中，我们建议对广泛耐药和广泛耐药前结核病参与者进行前瞻性队列研究，以确定对贝达奎林耐药的遗传机制。在产生耐药性的参与者中，我们将对结核分枝杆菌分离株进行全基因组测序，以确定与耐药性相关的基因多态。在目标2中，我们将研究贝达奎兰与ART的药物相互作用。根据对健康志愿者的小剂量单剂量研究，建议贝达奎林与奈韦拉平或基于洛皮那韦/利托那韦的方案一起服用。我们将对接受贝达奎林治疗的参与者进行密集和稀疏的药代动力学抽样，无论是否使用抗逆转录病毒治疗。在目标3中，我们将确定贝达奎林与其他延长QT的结核病药物一起使用的安全性。我们推测贝达奎林与氯法齐明或氟喹诺酮类药物联合应用将导致QT间期增加，并可能导致危及生命的QT延长，需要停用这些药物中的一种或多种。这项研究的每个目标都将回答关于贝达奎兰的一个基本问题，这将直接告知其在南非和全球的使用情况。我们的研究将从世界上最大的接受贝达奎兰治疗的患者的非试验队列中进行。美国国立卫生研究院和联邦结核病工作组已经为艾滋病毒和耐药结核病之间的相互作用确定了具体的优先研究领域。这项申请将集中在南非的两个这样的贝达奎兰区域--新的耐药性标记和与抗逆转录病毒药物的药理相互作用--南非是耐药结核病和艾滋病毒集中流行的中心。