Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration.
Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration.
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DOI：
10.1038/s41598-017-00529-6
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发表时间：
2017-03-29
影响因子：
4.6
通讯作者：
Biagini GA
中科院分区：
文献类型：
--
作者：
Aljayyoussi G;Jenkins VA;Sharma R;Ardrey A;Donnellan S;Ward SA;Biagini GA
结核病（TB）的治疗是长期和复杂的，通常涉及6个月的药物组合。迫切需要改进药物方案以缩短和简化治疗，然而结核病药物开发的主要挑战是缺乏预测性临床前工具。为了解决这一缺陷，我们采用了一种新的高内容成像方法，能够定义一线抗结核药物对巨噬细胞内胞内结核分枝杆菌（Mtb）的杀伤动力学。通过使用这种药代动力学-药效学（PK-PD）方法，我们证明了细胞内Mtb亚群的杀伤动力学对于预测临床TB治疗持续时间至关重要。细胞内Mtb杀伤与常规细胞外Mtb杀伤数据的综合建模产生了临床上描述的那些典型的双相反应。我们的模型支持使用较高剂量利福平（35 mg/kg）将显著缩短治疗持续时间的假设。我们描述的PK-PD方法为识别和优先考虑有可能缩短TB治疗持续时间的新疗法提供了急需的决策工具。
Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To address this deficiency, we have adopted a new high-content imaging-based approach capable of defining the killing kinetics of first line anti-TB drugs against intracellular Mycobacterium tuberculosis (Mtb) residing inside macrophages. Through use of this pharmacokinetic-pharmacodynamic (PK-PD) approach we demonstrate that the killing dynamics of the intracellular Mtb sub-population is critical to predicting clinical TB treatment duration. Integrated modelling of intracellular Mtb killing alongside conventional extracellular Mtb killing data, generates the biphasic responses typical of those described clinically. Our model supports the hypothesis that the use of higher doses of rifampicin (35 mg/kg) will significantly reduce treatment duration. Our described PK-PD approach offers a much needed decision making tool for the identification and prioritisation of new therapies which have the potential to reduce TB treatment duration.