PDF(Pubmed)
Abstract：
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.
摘要：
我们试图更好地了解食品和药物管理局（FDA）批准的抗生素用于社区适应症的感染动物模型的效用和作用。医院获得的-，和呼吸机相关细菌性肺炎（CABP，HABP,VABP),复杂性尿路感染（cUTI），复杂的腹腔内感染（cIAI），和急性细菌性皮肤和结构感染（ABSSSI）。我们回顾了2014-2019年FDA批准的抗生素新药申请（NDA）的相关文件。小鼠中性粒细胞减少大腿感染模型支持在11/12NDA中选择药代动力学-药效学（PKPD）靶标。与至少1-log细菌减少相关的PKPD靶标通常被认为是支持断点的理想靶标(10/12NDA)。血浆PK,与器官特异性PK相反，通常被认为是PKPD相关性最可靠的。断点确定是多学科的，至少对流行病学截断值进行核算，非临床PKPD，临床暴露反应和临床疗效。非临床PKPD目标结合目标达成概率(PTA)分析产生与流行病学截止值和临床衍生的断点一致的断点。在6/12NDA中，支持临床衍生断点的数据有限，因此,非临床PKPD靶标结合PTA分析在最终断点确定中发挥了更高的作用.赞助商和FDA的断点决定达成了共识。可能由于最佳PKPD指数的定义或从动物到人的外推蛋白质结合能力的差异而产生了分歧。总的来说,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目标确定的证据来支持所审查的NDA，玩,结合PTA分析，在标记目的的断点确定中具有重要作用。
