Understanding the drug exposure-response relationship of bedaquiline to predict efficacy for novel dosing regimens in the treatment of multidrug-resistant tuberculosis
Understanding the drug exposure-response relationship of bedaquiline to predict efficacy for novel dosing regimens in the treatment of multidrug-resistant tuberculosis
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DOI：
10.1111/bcp.14199
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发表时间：
2020-02-16
影响因子：
3.4
通讯作者：
Svensson, Elin M.
中科院分区：
文献类型：
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作者：
Tanneau, Lenaig;Karlsson, Mats O.;Svensson, Elin M.
目的从外部验证贝达喹啉暴露与较难治疗患者细菌负荷下降之间的早期特征关系，并通过模拟探索替代给药方案的性能。方法利用来自C209开放标签研究的233例新诊断或治疗经验的耐药结核病患者的阳性时间数据验证贝达喹啉暴露-反应关系。将暴露-反应关系对细菌清除率的意义与恒定药物效应模型进行比较。结核病耐药类型和抗结核前治疗的存在和持续时间作为附加协变量进行评估。模拟不同耐药类型肺结核患者的备选给药方案。结果高浓度的贝达喹啉与患者细菌负荷下降速度有关，暴露-效应关系明显优于恒定的药物效应（相对似然= 0.0003）。与耐多药结核病（MDR）患者相比，广泛耐药结核病（pre-XDR）患者的细菌清除半衰期延长22%，广泛耐药结核病（XDR）患者的半衰期延长86%。通过调整剂量和给药频率，可以使（前）广泛耐药结核病患者获得与耐多药结核病患者相同的治疗反应。此外，在ZeNix方案中，每日给药贝达喹啉预计与批准的方案一样有效。结论确定的贝达喹啉暴露-反应关系为预测替代给药方案下的疗效提供了可能，并为潜在的治疗方案优化提供了有用的工具。
Aims To externally validate an earlier characterized relationship between bedaquiline exposure and decline in bacterial load in a more difficult-to-treat patient population, and to explore the performances of alternative dosing regimens through simulations.Methods The bedaquiline exposure-response relationship was validated using time-to-positivity data from 233 newly diagnosed or treatment-experienced patients with drug-resistant tuberculosis from the C209 open-label study. The significance of the exposure-response relationship on the bacterial clearance was compared to a constant drug effect model. Tuberculosis resistance type and the presence and duration of antituberculosis pre-treatment were evaluated as additional covariates. Alternative dosing regimens were simulated for tuberculosis patients with different types of drug resistance.Results High bedaquiline concentrations were confirmed to be associated with faster bacterial load decline in patients, given that the exposure-effect relationship provided a significantly better fit than the constant drug effect (relative likelihood = 0.0003). The half-life of bacterial clearance was identified to be 22% longer in patients with pre-extensively drug-resistant (pre-XDR) tuberculosis (TB) and 86% longer in patients with extensively drug-resistant (XDR) TB, compared to patients with multidrug-resistant (MDR) TB. Achievement of the same treatment response for (pre-)XDR TB patients as for MDR TB patients would be possible by adjusting the dose and dosing frequency. Furthermore, daily bedaquiline administration as in the ZeNix regimen, was predicted to be as effective as the approved regimen.Conclusion The confirmed bedaquiline exposure-response relationship offers the possibility to predict efficacy under alternative dosing regimens, and provides a useful tool for potential treatment optimization.