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.

项目概要/摘要 结核性脑膜炎 (TBM) 是最严重的结核病形式，其后果在艾滋病毒携带者中尤其严重。 感染者的死亡率接近 60%，而幸存者往往会留下大量的生命。 神经功能障碍导致不良结果的原因之一是脑脊液中的药物浓度不足。 液体（CSF），包括标准剂量（10mg/kg）的利福平，这是几种主要的抗结核药物。 大量证据支持这样的假设：使用更高浓度的利福平可能会改善 TBM 的结果 剂量和添加利奈唑胺，其具有出色的脑脊液渗透性，这形成了部分理由。 2a 期随机对照试验 (LASER-TBM) 将评估 35mg/kg 利福平和 利奈唑胺用于患有 HIV 相关 TBM 的南非人（n = 100），为更大规模的疗效试验提供信息。 对大剂量利福平和利奈唑胺用于 TBM 的了解有限首先，血浆和脑脊液药代动力学。 （PK）以及对于剂量优化很重要的暴露-反应关系没有得到充分定义。 具体而言，蛋白质水平的动态变化对利福平脑脊液浓度的影响尚不清楚。 其次，尚不清楚口服高剂量利福平是否能达到与静脉注射治疗相似的暴露量， 第三，利福平和利奈唑胺之间可能存在药物相互作用。 降低利奈唑胺的治疗效果 该提案的科学目标是解决这些问题。 通过在 LASER-TBM 试验中表征高剂量利福平和利奈唑胺的 PK 来确定差距，目标是 为未来的疗效试验和临床实践提供治疗方法的具体目标是：（1） 描述利奈唑胺和高剂量利福平的血浆和脑脊液 PK，包括未结合的蛋白质浓度， 并评估暴露、疗效和毒性之间的关系；（2）研究药物间相互作用； 利福平和利福平之间的比较，以提供利福平对利福平暴露的影响的可靠估计； (3) 比较高剂量口服利福平与静脉注射利福平的血浆和脑脊液暴露量，以支持口服利福平的使用 该提案响应了临床试验和规划环境中的关键需求领域。 南非：与区域卫生优先事项和当地职业发展高度相关的研究； Sean Wasserman 博士是开普敦大学的一名传染病医生。 其职业目标是独立进行研究，为临床实践提供信息并最终减少 拟议的活动与他关于优化利奈唑胺治疗结核病的博士论文非常一致。 通过 PK 研究，制定全面的职业发展计划，包括结构化活动和 指导机会将促进 Wasserman 博士的培训目标，即获得以下方面的高级分析技能 药理学，包括药物的空间定量，以及临床试验设计、实施和实施方面的经验 该 K43 奖项将使他能够建立一个独立的结核病研究项目并进行分析。 影响撒哈拉以南非洲健康结果的药理学研究和临床试验。