Characterizing the pharmacokinetics of high dose rifampicin and linezolid in a randomized controlled trial for HIV-associated tuberculous meningitis

在 HIV 相关结核性脑膜炎随机对照试验中表征大剂量利福平和利奈唑胺的药代动力学

• 批准号: 10155617
• 负责人: Sean Adam Wasserman
• 金额: $ 10.34万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-27 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155617
• 关键词: ABCB1 gene; Accounting; Address; Adult; Affect; Africa South of the Sahara; Antibiotics; Antitubercular Agents; Area; Award; Binding Proteins; Biological Assay; Blood - brain barrier anatomy; CYP3A4 gene; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Clinical Trials; Clinical Trials Design; Collaborations; Communicable Diseases; Complement; Cytochromes; Data; Development Plans; Disease; Doctor of Philosophy; Dose; Drug Interactions; Drug Kinetics; Equilibrium; Evaluation; Exposure to; Failure; Funding; Future; Goals; HIV; HIV therapy; Health; Health Priorities; Hospitalization; Hydroxycholesterols; Intravenous; Knowledge; Lead; Left; Lesion; Linezolid; Meningeal Tuberculosis; Mentors; Mentorship; Modeling; Morbidity - disease rate; Neurologic; Oral; Oryctolagus cuniculus; Outcome; Pathogenesis; Patients; Penetration; Pharmaceutical Preparations; Phase; Physicians; Plasma; Positioning Attribute; Proteins; Pulmonary Tuberculosis; Randomized; Randomized Controlled Trials; Regimen; Research; Research Priority; Resources; Rifampin; Risk; Safety; Scientist; Site; South Africa; South African; Structure; Survivors; Therapeutic; Therapeutic Equivalency; Time; Toxic effect; Training; Tuberculosis; Universities; advanced analytics; antimicrobial; base; brain tissue; burden of illness; career; career development; clinical practice; clinically significant; cost; design; disability; drug distribution; drug-sensitive; efficacy trial; experience; improved; improved outcome; indexing; intravenous administration; mortality; novel; novel therapeutic intervention; pharmacometrics; pre-clinical; programs; response; skills; standard of care; training opportunity; tuberculosis drugs

PROJECT SUMMARY/ABSTRACT Tuberculous meningitis (TBM) is the most serious form of TB. Outcomes are particularly severe amongst HIV- infected patients, in whom the mortality approaches 60%, and survivors are frequently left with substantial neurological disability. One reason for poor outcomes is inadequate drug concentrations in the cerebrospinal fluid (CSF), including with standard doses (10mg/kg) of rifampicin, the key antituberculosis agent. Several lines of evidence support the hypothesis that outcomes in TBM may be improved with the use of higher rifampicin doses and the addition of linezolid, which has excellent CSF penetration. This forms partial rationale for a Phase 2a randomized controlled trial (LASER-TBM) which will evaluate the safety of 35mg/kg rifampicin and linezolid in South Africans with HIV-associated TBM (n = 100) to inform larger efficacy trials. However, knowledge of high dose rifampicin and linezolid for TBM is limited. First, plasma and CSF pharmacokinetics (PK) as well as exposure-response relationships, important for dose optimization, are inadequately defined. Specifically, the influence of dynamic changes in protein levels on rifampicin CSF concentrations is unknown. Second, it is unclear whether oral high dose rifampicin achieves similar exposures to intravenous therapy, planned for efficacy trials. Third, there is a drug-drug interaction between rifampicin and linezolid that may reduce the therapeutic benefit of linezolid. The scientific goal of this proposal is to address these knowledge gaps by characterizing the PK of high dose rifampicin and linezolid in the LASER-TBM trial, with the objective of informing the therapeutic approach for future efficacy trials and clinical practice. The specific aims are to: (1) describe plasma and CSF PK of linezolid and high dose rifampicin, including protein-unbound concentrations, and evaluate relationships between exposure, efficacy and toxicity; (2) investigate the drug-drug interaction between linezolid and rifampicin to provide a robust estimation of rifampicin effects on linezolid exposure; and (3) compare plasma and CSF exposures of high dose oral versus intravenous rifampicin to support use of oral rifampicin in clinical trials and in programmatic settings. This proposal is responsive to areas of critical need in South Africa: research that is highly relevant to regional health priorities; and career development of a local clinician-scientist. Dr. Sean Wasserman is an Infectious Diseases physician at the University of Cape Town with a career goal to independently conduct research that informs clinical practice and ultimately reduces the burden of disease. The proposed activities are well-aligned to his PhD on optimizing use of linezolid for TB through PK studies. A comprehensive career development plan comprising structured activities and mentorship opportunities will facilitate Dr. Wasserman’s training goals to acquire advanced analytical skills in pharmacometrics, including spatial quantitation of drugs, and experience in clinical trial design, conduct, and analysis. This K43 award will position him to build an independent program of research in TB and conduct pharmacometric studies and clinical trials that impact on health outcomes in sub-Saharan Africa.

项目摘要/摘要 结核性脑膜炎（TBM）是结核病最严重的形式。在艾滋病毒中，结果特别严重 - 感染的患者，死亡率接近60％，生存期经常保持大量 神经疾病。结果不佳的原因之一是脑脊液中的药物浓度不足 流体（CSF），包括利福平标准剂量（10mg/kg），主要抗结核剂。几行 证据支持以下假设，即使用更高的利福平可以改善TBM的结果 剂量和添加LineZolid，具有出色的CSF穿透。这构成了一个部分理由 2A阶段随机对照试验（Laser-TBM），将评估35mg/kg利福平的安全性和 与HIV相关的TBM（n = 100）的南非人的LineZolid为更大的效率试验提供了信息。然而， 对TBM的高剂量利福平和lineZolid的知识是有限的。首先，血浆和CSF药代动力学 （PK）以及对剂量优化重要的暴露响应关系的定义不足。 具体而言，蛋白质水平动态变化对利福平CSF浓度的影响尚不清楚。 其次，目前尚不清楚口服高剂量利福平是否能够获得类似的静脉治疗暴露， 计划进行有效的试验。第三，利福平和linezolid之间存在药物 - 可能的相互作用 降低lineZolid的治疗益处。该提议的科学目标是解决这些知识 通过在激光-TBM试验中表征高剂量利福平和linezolid的PK的间隙，目的 为未来效率试验和临床实践提供治疗方法的信息。具体目的是：（1） 描述linezolid和高剂量利福平的血浆和CSF PK，包括蛋白质 - 无浓度， 并评估暴露，效率和毒性之间的关系； （2）调查药物相互作用 在lineZolid和利福平之间，可以对利福平对线索酚暴露的影响进行强有力的估计；和 （3）比较高剂量口服与静脉里佛利台蛋白的血浆和CSF暴露以支持口服的使用 利福平在临床试验和程序化环境中。该提议对重要需求的领域有反应 南非：与区域卫生重点高度相关的研究；和当地的职业发展 临床科学家。肖恩·瓦瑟曼（Sean Wasserman）博士是开普敦大学的传染病医师 具有独立进行研究的职业目标，以为临床实践提供信息，并最终减少 疾病负担。提议的活动与他的博士学位相符，以优化使用LineZolid作为结核病 通过PK研究。一项全面的职业发展计划，完成结构化活动和 Menorship机会将促进Wasserman博士的培训目标，以获得高级分析技能 药物计量学，包括药物的空间定量以及临床试验设计，行为和 分析。这项K43奖将使他定位在结核病中建立独立的研究计划并进行 影响撒哈拉以南非洲健康结果的药物测量研究和临床试验。