Preclinical animal models of infection are employed to develop new agents but also to screen among molecules to rank them. There are often major differences between human pharmacokinetic (PK) profiles and those developed by animal models of infection, and these may lead to substantial differences in efficacy relative to that seen in humans. Linezolid is a repurposed agent employed to great effect for therapy of Mycobacterium tuberculosis. In this study, we used the hollow-fiber infection model (HFIM) to evaluate the impact of different pharmacokinetic profiles of mice and nonhuman primates (NHP) versus humans on bacterial cell kill as well as resistance suppression. We examined both plasma and epithelial lining fluid (ELF) profiles. We examined simulated exposures equivalent to 600 mg and 900 mg daily of linezolid in humans. For both plasma and ELF exposures, the murine PK profile provided estimates of effect that were biased low relative to human and NHP PK profiles. Mathematical modeling identified a linkage between minimum concentrations (C_min) and bacterial kill and peak concentrations (C_peak) and resistance suppression, with the latter being supported by a prospective validation study. Finding new agents with novel mechanisms of action against M. tuberculosis is difficult. It would be a tragedy to discard a new agent because of a biased estimate of effect in a preclinical animal system. The HFIM provides a system to benchmark evaluation of new compounds in preclinical animal model systems against human PK effects (species scale-up estimates of PK), to safeguard against unwarranted rejection of promising new agents.

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开发用于治疗结核分枝杆菌的新药：我们从临床前动物模型中获得什么信息？

临床前感染动物模型被用于开发新的药物，但也可以在分子中进行筛选以对其进行排名。人的药代动力学（PK）谱与感染动物模型所产生的谱之间通常存在重大差异，相对于人类所见，它们可能导致功效方面的实质性差异。利奈唑胺是用于结核分枝杆菌治疗的重用药物。在这项研究中，我们使用中空纤维感染模型（HFIM）评估了小鼠和非人类灵长类动物（NHP）与人类相比，不同药代动力学特征对细菌细胞杀伤和耐药性抑制的影响。我们检查了血浆和上皮内衬液（ELF）轮廓。我们检查了相当于人体每天600毫克和900毫克利奈唑胺的模拟暴露量。对于血浆和ELF暴露，鼠PK谱提供的效应估计相对于人和NHP PK谱偏低。数学模型确定了最低浓度（C _min）与细菌杀灭浓度和峰值浓度（C_{峰值）之间的联系。}）和阻力抑制，前瞻性验证研究支持后者。寻找具有新的抗结核分枝杆菌作用机制的药物是困难的。由于临床前动物系统中对效果的估计有偏差，因此放弃新药物将是一个悲剧。HFIM提供了一个系统，可以对临床前动物模型系统中的新化合物进行基准评估，以对抗人类PK效应（物种的PK放大估计），以防止不必要地排斥有希望的新药。