Pharmacodynamics and Bactericidal Activity of Combination Regimens in Pulmonary Tuberculosis: Application to Bedaquiline-Pretomanid-Pyrazinamide.
Pharmacodynamics and Bactericidal Activity of Combination Regimens in Pulmonary Tuberculosis: Application to Bedaquiline-Pretomanid-Pyrazinamide.
复制标题
肺结核联合治疗的药效学和杀菌活性：贝达喹啉-Pretomanid-吡嗪酰胺的应用。
DOI：
10.1128/aac.00898-22
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发表时间：
2022
影响因子：
4.9
通讯作者：
Lyons,MichaelA
中科院分区：
文献类型：
--
作者：
Lyons,MichaelA
结核病（TB）治疗方案共同开发的一个关键障碍是在早期临床试验中确定最佳药物和剂量组合的能力有限。虽然药代动力学-药效学（PKPD）目标实现是结核病药物疗效优化的主要工具，但PD目标是一个静态指标，无法区分单个药物对多药联合疗效的贡献。开发了用于治疗肺TB的贝达喹啉-pretomanid-吡嗪酰胺（BPaZ）的PKPD模型，作为方案开发的动态缓解-响应方法的一部分。该模型描述了血浆中药物浓度与其个体之间的时间过程关系，以及其对痰菌负荷的联合作用（通过固体培养物CFU计数和液体培养物阳性时间（TTP）评估）。使用来自2A期研究NC-001-（J-M-Pa-Z）和NC-003-（C-J-Pa-Z）的数据估计模型参数。结果包括表征BPaZ活性作为最敏感和最不敏感的吡嗪酰胺和贝达喹啉暴露的变化，分别与拮抗活性的BPa补偿的协同活性的BZ和PaZ。NC-003研究人群每日一次贝达喹啉200 mg、pretomanid 200 mg和吡嗪酰胺1,500 mg的模拟显示，BPaZ需要3个月才能在90%的受试者中达到液体培养阴性。BPaZ的这些结果旨在成为一个示例应用，其一般方法旨在从不断增长的新的和重新用途的结核病药物管道中获得全新的药物组合。
A critical barrier to codevelopment of tuberculosis (TB) regimens is a limited ability to identify optimal drug and dose combinations in early-phase clinical testing. While pharmacokinetic-pharmacodynamic (PKPD) target attainment is the primary tool for exposure-response optimization of TB drugs, the PD target is a static index that does not distinguish individual drug contributions to the efficacy of a multidrug combination. A PKPD model of bedaquiline-pretomanid-pyrazinamide (BPaZ) for the treatment of pulmonary TB was developed as part of a dynamic exposure-response approach to regimen development. The model describes a time course relationship between the drug concentrations in plasma and their individual as well as their combined effect on sputum bacillary load assessed by solid culture CFU counts and liquid culture time to positivity (TTP). The model parameters were estimated using data from the phase 2A studies NC-001-(J-M-Pa-Z) and NC-003-(C-J-Pa-Z). The results included a characterization of BPaZ activity as the most and least sensitive to changes in pyrazinamide and bedaquiline exposures, respectively, with antagonistic activity of BPa compensated by synergistic activity of BZ and PaZ. Simulations of the NC-003 study population with once-daily bedaquiline at 200 mg, pretomanid at 200 mg, and pyrazinamide at 1,500 mg showed BPaZ would require 3 months to attain liquid culture negativity in 90% of participants. These results for BPaZ were intended to be an example application with the general approach aimed at entirely novel drug combinations from a growing pipeline of new and repurposed TB drugs.