目的:结核病中空纤维系统(HFS-TB)是欧洲药品管理局认可的一种临床前模型,用于支持抗结核药物的开发过程。它可以模拟体内药代动力学(PK)-药效学(PD)属性的选定的抗菌药物,它可以输入到计算机模型中,为临床试验的设计提供信息。然而,历史数据和已发布的方案不足,并且省略了关键信息以使实验具有可重复性。因此,在这项工作中,我们的目标是优化和标准化各种HFS-TB操作程序。
方法:首先,我们用不同类型的中空纤维盒表征了细菌的生长动力学,结核分枝杆菌菌株和培养基。第二,我们模仿了中空纤维药筒内的莫西沙星PK曲线,以检查药物纤维相容性。最后,我们模拟人的莫西沙星总血浆PK曲线,每天一次口服400毫克后,以评估不同采样方法后的PK-PD,菌株,药筒大小和细菌适应期在药物注入系统之前。
结果:我们发现HFS-TB内的最终细菌负荷取决于所研究的变量。此外,我们证明了药物-纤维相容性测试是关键的初步HFS-TB检测,需要适当报告。最后,我们发现,采样方法和细菌适应期前的药物输注显著影响实际实验结论。
结论:我们的数据有助于HFS-TB实验的必要标准化,提请注意在报告新结果时应考虑的临床前模型的多个方面,并警告目前被忽视的HFS-TB的关键参数。
OBJECTIVE: The hollow‐fibre system for tuberculosis (HFS‐TB) is a preclinical model qualified by the European Medicines Agency to underpin the anti‐TB drug development process. It can mimic in vivo pharmacokinetic (PK)–pharmacodynamic (PD) attributes of selected antimicrobials, which could feed into in silico models to inform the design of clinical trials. However, historical data and published protocols are insufficient and omit key information to allow experiments to be reproducible. Therefore, in this work, we aim to optimize and standardize various HFS‐TB operational procedures.
METHODS: First, we characterized bacterial growth dynamics with different types of hollow‐fibre cartridges, Mycobacterium tuberculosis strains and media. Second, we mimicked a
moxifloxacin PK profile within hollow‐fibre cartridges, in order to check drug–fibres compatibility. Lastly, we mimicked the
moxifloxacin total plasma PK profile in human after once daily oral dose of 400 mg to assess PK–PD after different sampling methods, strains, cartridge size and bacterial adaptation periods before drug infusion into the system.
RESULTS: We found that final bacterial load inside the HFS‐TB was contingent on the studied variables. Besides, we demonstrated that drug–fibres compatibility tests are critical preliminary HFS‐TB assays, which need to be properly reported. Lastly, we uncovered that the sampling method and bacterial adaptation period before drug infusion significantly impact actual experimental conclusions.
CONCLUSIONS: Our data contribute to the necessary standardization of HFS‐TB experiments, draw attention to multiple aspects of this preclinical model that should be considered when reporting novel results and warn about critical parameters in the HFS‐TB currently overlooked.