Background The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the Phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes. Methods We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months, TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models, and all trial-defined safety outcomes using logistic regression. Results Our model derived rifampicin exposure ranged from 4.57 mg·h/L to 140.0 mg·h/L with a median of 41.8 mg·h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to weight-banded dose. Exposure-efficacy analysis (N=680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared to those with exposure above the median. Exposure-safety analysis (N=722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events, or serious adverse events. Conclusions Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard of care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation.

中文翻译：

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支持利福平固定剂量治疗结核病的 3 期试验的药代动力学-药效学证据

背景 利福平治疗药物敏感结核病 (TB) 的最佳剂量策略仍存在很大争议。在 3 期临床试验研究 31/ACTG 5349 (NCT02410772) 中，对照组的所有参与者每天接受 600 毫克利福平的固定剂量。在这里，我们评估了利福平暴露与疗效和安全性结果之间的关系。方法我们使用群体非线性混合效应模型分析利福平浓度时间曲线。我们比较了平带剂量和体重带剂量的模拟利福平暴露量。我们使用 Cox 比例风险模型评估了利福平暴露对 6 个月时稳定培养转化的影响，使用 Cox 比例风险模型评估了 9、12 和 18 个月时与结核病相关的不良结果，并使用逻辑回归评估了所有试验定义的安全结果。结果我们的模型得出的利福平暴露范围为 4.57 mg·h/L 至 140.0 mg·h/L，中位数为 41.8 mg·h/L。药代动力学模拟表明，固定剂量的利福平提供的暴露覆盖范围与体重区间剂量相似。暴露功效分析 (N=680) 显示，利福平暴露低于中位数的参与者与暴露于中位数以上的参与者相比，经历了类似的稳定培养转化和结核病相关不良结果的危险。暴露安全性分析（N=722）表明，利福平暴露量增加与3级或以上不良事件或严重不良事件增加无关。结论 利福平每日 600 mg 的固定剂量可能是 6 个月标准护理方案中现行体重带剂量策略的合理替代方案。未来的研究应评估利福平的最佳剂量策略，剂量高于目前的推荐剂量。