Predictive Modeling to Study the Treatment-Shortening Potential of Novel Tuberculosis Drug Regimens, Toward Bundling of Preclinical Data.
Predictive Modeling to Study the Treatment-Shortening Potential of Novel Tuberculosis Drug Regimens, Toward Bundling of Preclinical Data.
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DOI：
10.1093/infdis/jiab101
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发表时间：
2022-06-01
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鉴于结核病的全球负担持续很高，需要有效和较短的治疗选择。我们利用小鼠结核感染模型和数学模型探讨了复发与治疗时间的关系以及2种新型抗结核药物方案的方案间差异。 结核分枝杆菌感染的小鼠用贝达喹啉和pretomanid联合阿氟沙星和吡嗪酰胺（BPaMZ）或利奈唑胺（BPaL）治疗长达13周。治疗完成后12周评价治愈率。将异烟肼、利福平、吡嗪酰胺和乙胺丁醇（HRZE）的标准方案作为对照进行评价。六周的BPaMZ足以在所有小鼠中实现治愈。相比之下，13周的BPaL和24周的HRZE并没有达到100%的治愈率。根据数学模型预测，BPaMZ、BPaL和HRZE分别在1.6、4.3和7.9个月时预测治愈概率为95%。本研究为BPaMZ的治疗缩短能力优于BPaL和HRZE提供了额外的证据。为了最佳地使用临床前数据来预测临床结果，并克服阻碍这种外推的限制，我们主张将可用的已发表临床前数据捆绑到数学模型中。通过将小鼠结核病感染模型中抗结核药物方案的治疗效果评价与数学建模相结合，发现与标准HRZE方案相比，BPaMZ具有比BPaL更高的治疗缩短潜力。
Given the persistently high global burden of tuberculosis, effective and shorter treatment options are needed. We explored the relationship between relapse and treatment length as well as interregimen differences for 2 novel antituberculosis drug regimens using a mouse model of tuberculosis infection and mathematical modeling. Mycobacterium tuberculosis–infected mice were treated for up to 13 weeks with bedaquiline and pretomanid combined with moxifloxacin and pyrazinamide (BPaMZ) or linezolid (BPaL). Cure rates were evaluated 12 weeks after treatment completion. The standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was evaluated as a comparator. Six weeks of BPaMZ was sufficient to achieve cure in all mice. In contrast, 13 weeks of BPaL and 24 weeks of HRZE did not achieve 100% cure rates. Based on mathematical model predictions, 95% probability of cure was predicted to occur at 1.6, 4.3, and 7.9 months for BPaMZ, BPaL, and HRZE, respectively. This study provides additional evidence for the treatment-shortening capacity of BPaMZ over BPaL and HRZE. To optimally use preclinical data for predicting clinical outcomes, and to overcome the limitations that hamper such extrapolation, we advocate bundling of available published preclinical data into mathematical models. By combining the evaluation of treatment efficacy of anti-tuberculosis drug regimens in a mouse tuberculosis infection model with mathematical modeling, it was found that BPaMZ had a higher treatment-shortening potential than BPaL, compared to the standard HRZE regimen.
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