Selig Daniel, Caridha Diana, Evans Martin, Kress Adrian, Lanteri Charlotte, Ressner Roseanne, DeLuca Jesse
Walter Reed Army Institute of Research, Experimental Therapeutics, Silver Spring, MD 20910, USA.
J Pers Med. 2024 Jan 19;14(1):111. doi: 10.3390/jpm14010111.
We sought to better understand the utility and role of animal models of infection for Food and Drug Administration (FDA)-approved antibiotics for the indications of community-, hospital-acquired-, and ventilator-associated bacterial pneumonia (CABP, HABP, VABP), complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), and acute bacterial skin and structural infections (ABSSSIs). We reviewed relevant documents from new drug applications (NDA) of FDA-approved antibiotics from 2014-2019 for the above indications. Murine neutropenic thigh infection models supported the choice of a pharmacokinetic-pharmacodynamic (PKPD) target in 11/12 NDAs reviewed. PKPD targets associated with at least a 1-log bacterial decrease were commonly considered ideal (10/12 NDAs) to support breakpoints. Plasma PK, as opposed to organ specific PK, was generally considered most reliable for PKPD correlation. Breakpoint determination was multi-disciplinary, accounting at minimum for epidemiologic cutoffs, non-clinical PKPD, clinical exposure-response and clinical efficacy. Non-clinical PKPD targets in combination with probability of target attainment (PTA) analyses generated breakpoints that were consistent with epidemiologic cutoffs and clinically derived breakpoints. In 6/12 NDAs, there was limited data to support clinically derived breakpoints, and hence the non-clinical PKPD targets in combination with PTA analyses played a heightened role in the final breakpoint determination. Sponsor and FDA breakpoint decisions were in general agreement. Disagreement may have arisen from differences in the definition of the optimal PKPD index or the ability to extrapolate protein binding from animals to humans. Overall, murine neutropenic thigh infection models supported the reviewed NDAs by providing evidence of pre-clinical efficacy and PKPD target determination, and played, in combination with PTA analysis, a significant role in breakpoint determination for labeling purposes.
我们试图更好地了解动物感染模型对于美国食品药品监督管理局（FDA）批准用于社区获得性、医院获得性和呼吸机相关性细菌性肺炎（CABP、HABP、VABP）、复杂性尿路感染（cUTI）、复杂性腹腔内感染（cIAI）以及急性细菌性皮肤和皮肤结构感染（ABSSSI）适应症的抗生素的效用和作用。我们回顾了2014年至2019年FDA批准的用于上述适应症的抗生素新药申请（NDA）的相关文件。在审查的12份NDA中，有11份的小鼠中性粒细胞减少大腿感染模型支持了药代动力学-药效学（PKPD）靶点的选择。与细菌数量至少减少1个对数相关的PKPD靶点通常被认为是支持断点的理想靶点（12份NDA中有10份）。与器官特异性药代动力学相反，血浆药代动力学通常被认为对于PKPD相关性最为可靠。断点的确定是多学科的，至少要考虑流行病学临界值、非临床PKPD、临床暴露-反应和临床疗效。非临床PKPD靶点与靶点达成概率（PTA）分析相结合产生的断点与流行病学临界值和临床得出的断点一致。在12份NDA中有6份，支持临床得出断点的数据有限，因此非临床PKPD靶点与PTA分析相结合在最终断点确定中发挥了更大的作用。申办方和FDA的断点决定总体上是一致的。分歧可能源于最佳PKPD指数定义的差异或从动物外推至人类蛋白质结合的能力差异。总体而言，小鼠中性粒细胞减少大腿感染模型通过提供临床前疗效和PKPD靶点确定的证据，支持了所审查的NDA，并与PTA分析相结合，在用于标签目的的断点确定中发挥了重要作用。
