Institute for Therapeutic Innovation, College of Medicine, University of Florida, Gainesville, Florida, USA
Institute for Therapeutic Innovation, College of Medicine, University of Florida, Gainesville, Florida, USA.
Antimicrob Agents Chemother. 2020 Nov 17;64(12). doi: 10.1128/AAC.01376-20.
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 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 () and bacterial kill and peak concentrations () and resistance suppression, with the latter being supported by a prospective validation study. Finding new agents with novel mechanisms of action against 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.
感染的临床前动物模型用于开发新的药物，也用于筛选分子以对其进行排序。人类药代动力学（PK）曲线与感染动物模型的 PK 曲线之间常常存在很大差异，这可能导致药物的疗效与在人体中观察到的疗效有很大差异。利奈唑胺是一种重新利用的药物，在治疗感染方面效果显著。在这项研究中，我们使用中空纤维感染模型（HFIM）来评估不同的动物模型（小鼠和非人灵长类动物）和人类的 PK 曲线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衬里液（ELF）的 PK 曲线。我们模拟了相当于人类每天 600mg 和 900mg 利奈唑胺的暴露量。对于血浆和 ELF 暴露，鼠类 PK 曲线提供的效应估计值相对于人类和非人灵长类动物 PK 曲线存在低估。数学模型确定了最低浓度（Cmin）和细菌杀伤之间的联系，以及最高浓度（Cmax）和耐药性抑制之间的联系，后者得到了前瞻性验证研究的支持。找到针对的新型作用机制的新型药物非常困难。由于在临床前动物系统中对效应的估计存在偏差而放弃一种新型药物将是一场悲剧。HFIM 提供了一种系统，可以根据人类 PK 效应（物种 PK 放大估计值）来比较新化合物在临床前动物模型系统中的评估，以防止不合理地拒绝有前途的新型药物。
