印度尼西亚结核性脑膜炎试验中利福平暴露与死亡率的基于模型的meta分析。

Elin M Svensson, Sofiati Dian, Lindsey Te Brake, Ahmad Rizal Ganiem, Vycke Yunivita, Arjan van Laarhoven, Reinout Van Crevel, Rovina Ruslami, Rob E Aarnoutse
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引用次数: 45

摘要

背景:加强抗菌治疗,提高利福平剂量可改善结核性脑膜炎的预后,但理想暴露量和必要剂量尚不清楚。我们的目的是表征利福平暴露与死亡率之间的关系,以确定结核性脑膜炎的最佳剂量。方法:对印度尼西亚3项随机对照2期试验的数据进行个体患者荟萃分析,比较口服利福平450 mg (~10 mg/kg)和强化方案,包括750-1350 mg口服或600 mg静脉输注。采用非线性混合效应模型对血浆和脑脊液的药代动力学数据进行分析。6个月生存率用参数时间-事件模型描述。结果:药代动力学分析包括133个个体(1150个浓度测量,170个来自CSF)。最终模型具有2个处置隔间,可饱和间隙和自动感应。利福平脑脊液浓度用分配系数(5.5%;95%可信区间[CI], 4.5%-6.4%)和分配血浆到脑脊液的半衰期(2.1小时;95% CI, 1.3-2.9小时)。脑脊液蛋白浓度越高,分割系数越高。148人的生存(58人死亡,15人退出)的风险呈指数下降,年龄越低,基线格拉斯哥昏迷评分越高,个体利福平血浆暴露越多,风险越低。模拟预测,将口服利福平剂量从10 mg/kg增加到30 mg/kg后,6个月生存率将从约50%增加到约70%,并预测更高剂量将进一步提高生存率。结论:较高的利福平暴露量可显著降低死亡风险,在研究范围内未达到最大效果。我们建议在3期临床试验中研究至少30 mg/kg的利福平剂量。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Model-Based Meta-analysis of Rifampicin Exposure and Mortality in Indonesian Tuberculous Meningitis Trials.

Background: Intensified antimicrobial treatment with higher rifampicin doses may improve outcome of tuberculous meningitis, but the desirable exposure and necessary dose are unknown. Our objective was to characterize the relationship between rifampicin exposures and mortality in order to identify optimal dosing for tuberculous meningitis.

Methods: An individual patient meta-analysis was performed on data from 3 Indonesian randomized controlled phase 2 trials comparing oral rifampicin 450 mg (~10 mg/kg) to intensified regimens including 750-1350 mg orally, or a 600-mg intravenous infusion. Pharmacokinetic data from plasma and cerebrospinal fluid (CSF) were analyzed with nonlinear mixed-effects modeling. Six-month survival was described with parametric time-to-event models.

Results: Pharmacokinetic analyses included 133 individuals (1150 concentration measurements, 170 from CSF). The final model featured 2 disposition compartments, saturable clearance, and autoinduction. Rifampicin CSF concentrations were described by a partition coefficient (5.5%; 95% confidence interval [CI], 4.5%-6.4%) and half-life for distribution plasma to CSF (2.1 hours; 95% CI, 1.3-2.9 hours). Higher CSF protein concentration increased the partition coefficient. Survival of 148 individuals (58 died, 15 dropouts) was well described by an exponentially declining hazard, with lower age, higher baseline Glasgow Coma Scale score, and higher individual rifampicin plasma exposure reducing the hazard. Simulations predicted an increase in 6-month survival from approximately 50% to approximately 70% upon increasing the oral rifampicin dose from 10 to 30 mg/kg, and predicted that even higher doses would further improve survival.

Conclusions: Higher rifampicin exposure substantially decreased the risk of death, and the maximal effect was not reached within the studied range. We suggest a rifampicin dose of at least 30 mg/kg to be investigated in phase 3 clinical trials.

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