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: 9132486
• 负责人: James C M Brust
• 金额: $ 33.11万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 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 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132486
• 关键词: Advisory Committees; African; Anti-Retroviral Agents; Area; Arrhythmia; Biological Assay; CYP3A4 gene; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Clinical Trials; Code; Cohort Studies; Data; Development; Dose; Drug Interactions; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Drug usage; Effectiveness; Electrocardiogram; Epidemic; Excess Mortality; Extreme drug resistant tuberculosis; Fluoroquinolones; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genome; HIV; HIV Seropositivity; HIV drug resistance; Health; Individual; Lead; Letters; Lopinavir/Ritonavir; Medicine; Molecular; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mutation; Mycobacterium tuberculosis; Nevirapine; Operon; Outcome; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plasma; Population; Prevalence; Property; Proteins; Publishing; Regimen; Reporting; Research Priority; Resistance; Resistance development; Risk; Safety; Sampling; Single Nucleotide Polymorphism; South Africa; Therapeutic; Time; Torsades de Pointes; Toxic effect; Treatment Failure; Treatment outcome; Tuberculosis; United States National Institutes of Health; World Health Organization; antiretroviral therapy; base; clinically significant; co-infection; cohort; drug mechanism; fighting; genome sequencing; healthy volunteer; high risk; improved; mortality; novel; novel marker; novel therapeutics; patient population; phase 2 study; prospective; resistance mechanism; success; tool; 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 persons. 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 patients with 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 safety of this potentially transformative drug, the mechanisms of resistance, and the potential drug-drug interactions with common antiretroviral drugs. 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 pre-XDR and 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 pre-XDR and XDR TB participants to determine the effect of bedaquiline on the QT-interval when given 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 dangerous QT prolongation requiring discontinuation of one or more of these medications. In Aim 2, we will use whole genome sequencing 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 single nucleotide polymorphisms (SNPs). In Aim 3, 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. 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）已成为一种重要的全球流行病，对艾滋病毒感染者构成特别威胁。由于缺乏有效的治疗药物，XDR结核病的死亡率极高。贝达喹啉是40年来第一个获得FDA批准的结核病新药，在耐多药结核病患者的早期临床试验中显示出相当大的前景。然而，该药物尚未在XDR TB患者或正在接受抗逆转录病毒治疗（ART）的HIV合并感染患者中进行充分研究。因此，关于这种潜在的变革性药物的安全性、耐药机制以及与常见抗逆转录病毒药物的潜在药物相互作用，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合并感染的迅速蔓延。2013年，国家卫生部制定了一项治疗计划，使贝达喹啉与优化的背景方案相结合，可用于前XDR和XDR结核病患者。南非的XDR结核病和艾滋病病毒的碰撞提供了一个独特的机会，可以在可能从中获益的患者中研究贝达喹啉，但这些患者在很大程度上被排除在临床试验之外。 在目标1中，我们提出了一项XDR前和XDR TB受试者的前瞻性队列研究，以确定贝达喹啉与其他QT延长TB药物联合给药时对QT间期的影响。我们假设贝达喹啉与氯法齐明或氟喹诺酮类药物联合给药将导致QT间期叠加性增加，并可能导致危险的QT间期延长，需要停用一种或多种这些药物。在目标2中，我们将使用全基因组测序来确定贝达喹啉耐药的遗传机制。在产生耐药性的参与者中，我们将进行M的全基因组测序。结核病分离株，以确定单核苷酸多态性（SNP）。在目标3中，我们将研究贝达喹啉与ART的药物相互作用。根据在健康志愿者中进行的小型单次给药研究，建议贝达喹啉与奈韦拉平或洛匹那韦/利托那韦为基础的方案联合给药。我们将对接受贝达喹啉治疗的受试者进行密集和稀疏的药代动力学采样，无论是否接受ART。本研究的每一个目的都将回答关于贝达喹啉的一个基本问题，这将直接影响其在南非和全球的使用。我们的研究将从世界上最大的接受贝达喹啉治疗的非试验患者队列中抽取样本。美国国立卫生研究院和联邦结核病工作组已经确定了艾滋病毒和耐药结核病之间相互作用的具体优先研究领域。这项申请将集中在两个这样的领域贝达喹啉-新的耐药标志物和与ART的药理学相互作用-在南非，耐药结核病和艾滋病毒的集中流行的中心。