Abdelgawad Noha, Wasserman Sean, Gausi Kamunkhwala, Davis Angharad, Stek Cari, Wiesner Lubbe, Meintjes Graeme, Wilkinson Robert J, Denti Paolo
Division of Clinical Pharmacology, Department of Medicine.
Wellcome Discovery Research Platforms for Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South Africa.
J Infect Dis. 2025 Apr 29. doi: 10.1093/infdis/jiaf178.
Several ongoing clinical trials are evaluating high-dose rifampicin (up to 35 mg/kg) for tuberculous meningitis (TBM). However, rifampicin pharmacokinetics at higher doses is not fully characterized, particularly in cerebrospinal fluid (CSF), the site of TBM disease.
In a randomized controlled trial, adults with HIV-associated TBM were assigned to experimental arms of high-dose rifampicin (oral, 35 mg/kg; intravenous, 20 mg/kg) plus linezolid, with or without aspirin, or a control arm that received the standard of care with 10 mg/kg of oral rifampicin. Rifampicin concentrations, including the unbound fraction, were measured on plasma samples, and CSF was collected on days 3 and 28 of study enrollment. Data were analyzed by nonlinear mixed effects modeling.
In total, 400 plasma and 44 CSF rifampicin concentrations from 48 participants were used for model development. The median (range) age and weight were 39 years (25-78) and 60 kg (30-107). Rifampicin pharmacokinetics was best described by a 2-compartment disposition model with first-order transit oral absorption and elimination via saturable hepatic extraction. Typical clearance values for the standard dose for days 3 and 28 were 33.1 and 41.4 L/h, respectively; high-dose values were 46.1 and 70.2 L/h. The CSF-plasma ratio was approximately 6% and the equilibration half-life was 3.2 hours. Simulated standard-dose rifampicin did not reach CSF concentrations above the critical concentration for Mycobacterium tuberculosis.
CSF penetration with standard-dose rifampicin is low. Our findings support continued evaluation of high-dose rifampicin for TBM treatment.
多项正在进行的临床试验正在评估高剂量利福平（高达35mg/kg）用于结核性脑膜炎（TBM）的疗效。然而，更高剂量下利福平的药代动力学尚未完全明确，尤其是在TBM疾病发生部位脑脊液（CSF）中的情况。
在一项随机对照试验中，将成人HIV相关TBM患者分配至高剂量利福平（口服，35mg/kg；静脉注射，20mg/kg）联合利奈唑胺的试验组，试验组加用或不加用阿司匹林，或分配至接受10mg/kg口服利福平标准治疗的对照组。在血浆样本上测量利福平浓度，包括游离分数，并在研究入组的第3天和第28天收集脑脊液。通过非线性混合效应模型分析数据。
总共使用了48名参与者的400份血浆和44份脑脊液利福平浓度进行模型开发。年龄中位数（范围）为39岁（25 - 78岁），体重中位数（范围）为60kg（30 - 107kg）。利福平的药代动力学最好用具有一级转运口服吸收和通过饱和肝提取消除的二室处置模型来描述。第3天和第28天标准剂量的典型清除率值分别为33.1L/h和41.4L/h；高剂量值为46.1L/h和70.2L/h。脑脊液与血浆的比率约为6%，平衡半衰期为3.2小时。模拟的标准剂量利福平未达到高于结核分枝杆菌临界浓度的脑脊液浓度。
标准剂量利福平的脑脊液穿透率较低。我们的研究结果支持继续评估高剂量利福平用于TBM治疗。
