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

项目摘要/摘要 结核脑膜炎(TBM)是最严重的结核病形式。结果在艾滋病毒中尤其严重- 感染患者，其中死亡率接近60%，幸存者经常留下大量的 神经性残疾。预后不佳的一个原因是脑脊液中药物浓度不足。 液体(脑脊液)，包括标准剂量(10毫克/公斤)的利福平，关键的抗结核药物。几行 大量证据支持这样一种假设，即使用较高剂量的利福平可改善结缔组织病的预后 剂量和添加利奈唑胺，具有良好的脑脊液渗透。这形成了一种 2a期随机对照试验(LASER-TBM)，将评估35 mg/kg利福平和 利奈唑胺在南非HIV相关TBM患者(n=100)中的应用，为更大规模的疗效试验提供信息。然而， 关于大剂量利福平和利奈唑胺治疗TBM的知识有限。第一，血浆和脑脊液的药代动力学 (Pk)以及对剂量优化很重要的暴露-反应关系没有得到充分的定义。 具体地说，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，目前尚不清楚口服大剂量利福平是否与静脉治疗有类似的暴露， 计划进行疗效试验。第三，利福平和利奈唑胺之间存在药物-药物相互作用，可能 降低利奈唑胺的治疗效果。这项提议的科学目标是解决这些知识 激光-TBM试验中表征大剂量利福平和利奈唑胺PK的差距 为未来的疗效试验和临床实践提供治疗方法的信息。具体目标是：(1) 描述利奈唑胺和大剂量利福平的血浆和脑脊液PK，包括蛋白未结合浓度， 评价暴露、疗效和毒性之间的关系；(2)研究药物与药物的相互作用 利奈唑胺和利福平之间的关系，以提供利福平对利奈唑胺暴露的影响的可靠估计；以及 (3)比较大剂量口服利福平和静脉注射利福平的血浆和脑脊液暴露，以支持口服 利福平在临床试验和规划环境中。这项提议是对#年的迫切需要作出反应的。 南非：与区域卫生优先事项高度相关的研究；以及当地职业发展 临床医生兼科学家。肖恩·沃瑟曼博士是开普敦大学传染病内科医生 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 疾病的负担。建议的活动与他关于优化利奈唑胺治疗结核病的博士学位相一致 通过PK学习。全面的职业发展计划，包括有组织的活动和 指导机会将有助于沃瑟曼博士的培训目标在以下方面获得高级分析技能 药物计量学，包括药物的空间定量，以及临床试验设计、实施和 分析。这项K43奖项将使他能够建立一个独立的结核病研究计划并进行 影响撒哈拉以南非洲健康结果的药物计量研究和临床试验。

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.