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: 10396033
• 负责人: Sean Adam Wasserman
• 金额: $ 10.78万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396033
• 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; Persons; Pharmaceutical Preparations; Phase; Physicians; Plasma; Positioning Attribute; Proteins; Pulmonary Tuberculosis; Randomized; Randomized Controlled Trials; Regimen; Research; Research Priority; Resource-limited setting; 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.

项目总结/摘要 结核性脑膜炎（TBM）是最严重的结核病。艾滋病毒感染者的后果尤其严重- 感染的病人，其中死亡率接近60%，幸存者往往留下大量的 神经性残疾结果不佳的一个原因是脑脊液中药物浓度不足 液体（CSF），包括标准剂量（10 mg/kg）的利福平（关键抗结核药物）。几行 的证据支持这一假设，即使用更高剂量的利福平可改善TBM的结局 剂量和添加利奈唑胺，其具有优异的CSF渗透性。这构成了 2a期随机对照试验（LASER-TBM），将评价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，以指导更大规模的疗效试验。然而，在这方面， 对于TBM的大剂量利福平和利奈唑胺的认识有限。首先，血浆和CSF药代动力学 (PK)以及对剂量优化很重要的剂量-反应关系也没有充分定义。 具体而言，蛋白水平的动态变化对利福平CSF浓度的影响尚不清楚。 其次，口服高剂量利福平是否达到与静脉治疗相似的暴露量尚不清楚， 计划进行疗效试验。第三，利福平和利奈唑胺之间存在药物相互作用， 降低利奈唑胺的治疗获益。这项提案的科学目标是解决这些知识 通过表征LASER-TBM试验中高剂量利福平和利奈唑胺的PK， 为未来的疗效试验和临床实践提供治疗方法。具体目标是：（1） 描述利奈唑胺和高剂量利福平的血浆和CSF PK，包括蛋白质未结合浓度， 并评价暴露、疗效和毒性之间的关系;（2）研究药物间的相互作用 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量影响的稳健估计;以及 (3)比较高剂量口服与静脉注射利福平的血浆和CSF暴露量，以支持使用口服 利福平在临床试验和规划设置。这项建议是为了满足下列领域的迫切需要： 南非：与区域卫生优先事项高度相关的研究;以及一名当地人的职业发展 临床科学家Sean Wasserman博士是开普敦大学的传染病医生 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 疾病负担。拟议的活动与他关于优化利奈唑胺治疗结核病的博士学位完全一致 通过PK研究。全面的职业发展计划，包括结构化的活动， 导师的机会将促进博士沃瑟曼的培训目标，以获得先进的分析技能， 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.这个K43奖将使他能够建立一个独立的结核病研究项目， 药物计量学研究和临床试验对撒哈拉以南非洲的健康结果产生影响。

项目成果

Clinical features and outcomes of COVID-19 admissions in a population with a high prevalence of HIV and tuberculosis: a multicentre cohort study.

• DOI: 10.1186/s12879-022-07519-8
• 发表时间: 2022-06-20
• 期刊: BMC INFECTIOUS DISEASES
• 影响因子: 3.7
• 作者: Parker, Arifa;Boloko, Linda;Moolla, Muhammad S.;Ebrahim, Nabilah;Ayele, Birhanu T.;Broadhurst, Alistair G. B.;Mashigo, Boitumelo;Titus, Gideon;de Wet, Timothy;Boliter, Nicholas;Rosslee, Michael-Jon;Papavarnavas, Nectarios;Abrahams, Riezaah;Mendelson, Marc;Dlamini, Sipho;Taljaard, Jantjie J.;Prozesky, Hans W.;Mowlana, Abdurasiet;Viljoen, Abraham J.;Schrueder, Neshaad;Allwood, Brian W.;Lalla, Usha;Dave, Joel A.;Calligaro, Greg;Levin, Dion;Maughan, Deborah;Ntusi, Ntobeko A. B.;Nyasulu, Peter S.;Meintjes, Graeme;Koegelenberg, Coenraad F. N.;Mnguni, Ayanda T.;Wasserman, Sean
• 通讯作者: Wasserman, Sean

Emerging and re-emerging fungal threats in Africa.

• DOI: 10.1111/pim.12953
• 发表时间: 2023-02
• 期刊: PARASITE IMMUNOLOGY
• 影响因子: 2.2
• 作者: Dangarembizi, Rachael;Wasserman, Sean;Hoving, Jennifer Claire
• 通讯作者: Hoving, Jennifer Claire

COVID-19: Convalescent plasma as a potential therapy.

• DOI: 10.7196/samj.2020.v110i7.14983
• 发表时间: 2020-06
• 期刊: South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde
• 作者: K. V. D. Berg;M. Vermeulen;T. Glatt;S. Wasserman;C. Barrett;J. Peter;D. Brittain;V. Louw

A Phase 2A Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid, With or Without Aspirin, for Human Immunodeficiency Virus-Associated Tuberculous Meningitis: The LASER-TBM Trial.

• DOI: 10.1093/cid/ciac932
• 发表时间: 2023-04-17
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis.

Covid-19 患者强化预防性抗凝治疗与标准预防性抗凝治疗的疗效和安全性：系统评价和荟萃分析。

• DOI: 10.1101/2022.03.05.22271947
• 发表时间: 2022
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Wills,NicolaK;Nair,Nikhil;Patel,Kashyap;Sikder,Omaike;Adriaanse,Marguerite;Eikelboom,John;Wasserman,Sean
• 通讯作者: Wasserman,Sean