Department of Bioengineering and Therapeutic Sciences, University of California San Francisco Schools of Pharmacy and Medicine, San Francisco, California, USA.
UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, California, USA.
Clin Infect Dis. 2023 Jun 8;76(11):1903-1910. doi: 10.1093/cid/ciad051.
Safer, better, and shorter treatments for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are an urgent global health need. The phase 3 clinical trial Nix-TB (NCT02333799) tested a 6-month treatment of MDR and XDR-TB consisting of high-dose linezolid, bedaquiline, and pretomanid (BPaL). In this study, we investigate the relationship between the pharmacokinetic characteristics of the drugs, patient characteristics and efficacy endpoints from Nix-TB.
Pharmacokinetic data were collected at weeks 2, 8, and 16. Efficacy endpoints including treatment outcomes, time to stable culture conversion, and longitudinal time to positivity in the mycobacterial growth indicator tube assay were each characterized using nonlinear mixed-effects modeling. Relationships between patient, treatment pharmacokinetics, and disease characteristics and efficacy endpoints were evaluated.
Data from 93 (85% of the total) participants were analyzed. Higher body mass index was associated with a lower incidence of unfavorable treatment outcomes. Median time to stable culture conversion was 3 months in patients with lower baseline burden compared with 4.5 months in patients with high baseline burden. Participants with minimal disease had steeper time to positivity trajectories compared with participants with high-risk phenotypes. No relationship between any drugs' pharmacokinetics (drug concentration or exposure metrics) and any efficacy outcomes was observed.
We have successfully described efficacy endpoints of a BPaL regimen from the Nix-TB trial. Participants with high-risk phenotypes significantly delayed time to culture conversion and bacterial clearance. The lack of a relationship between pharmacokinetic exposures and pharmacodynamic biomarkers opens the possibility to use lower, safer doses, particularly for toxicity-prone linezolid.
NCT02333799.
对于耐多药（MDR）和广泛耐药（XDR）结核病（TB），更安全、更有效和疗程更短的治疗方法是全球迫切需要的。3 期临床试验 Nix-TB（NCT02333799）测试了一种 6 个月的 MDR 和 XDR-TB 治疗方案，该方案由高剂量利奈唑胺、贝达喹啉和普托马尼（BPaL）组成。在这项研究中，我们调查了 Nix-TB 中药物的药代动力学特征、患者特征和疗效终点之间的关系。
在第 2、8 和 16 周收集药代动力学数据。疗效终点包括治疗结果、稳定培养物转化的时间和分枝杆菌生长指示剂管测定中的纵向阳性时间，每个终点都用非线性混合效应模型进行描述。评估了患者、治疗药代动力学、疾病特征与疗效终点之间的关系。
对 93 名（总人数的 85%）参与者的数据进行了分析。较高的体重指数与不良治疗结果的发生率较低有关。与基线负担较高的患者相比，基线负担较低的患者稳定培养物转化的中位时间为 3 个月，而基线负担较高的患者为 4.5 个月。疾病负担较小的患者与高危表型的患者相比，时间到阳性的轨迹更陡峭。未观察到任何药物的药代动力学（药物浓度或暴露指标）与任何疗效结果之间存在关系。
我们成功地描述了 Nix-TB 试验中 BPaL 方案的疗效终点。高危表型的患者显著延迟了培养物转化和细菌清除的时间。药代动力学暴露与药效动力学生物标志物之间缺乏关系为使用更低、更安全的剂量提供了可能性，特别是对于毒性倾向的利奈唑胺。
NCT02333799。
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