Colistimethate Dose Optimization in Infants and Children

项目I“婴幼儿应用氨甲环己酯剂量优化 本项目旨在确定从足月婴儿到青少年，儿童患者体内氨甲环己酯(甲烷磺化前体药物)和粘菌素的药代动力学随年龄的变化。我们认为，氨甲环己酯和粘菌素在药物处理方面的发展变化足够大，足以保证在儿科亚群中采用不同的剂量指南。通过测量Cmax、T1/2、Vd、CL和AUC，通过对稀疏血浆采样技术得出的数据进行总体分析，并评估年龄、体重、身体表面积和肾功能的协变量，我们将能够根据在成人和实验动物中研究的暴露情况，成功地描述每个不同年龄段的儿科临床和微生物治疗所需的有效和安全剂量。通过分析氨甲环己酯和粘菌素在给药后的安全性，特别关注一系列肾脏毒性标记物，从标准的尿肌酐和白蛋白分析，到更复杂的肾脏损伤标记物，包括跨膜肾小管蛋白肾损伤分子-1(Kim-1)、β2-微球蛋白、视网膜B蛋白和尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)。我们希望按儿科年龄组详细描述使用氨甲环己酯和粘菌素可能发生的肾损伤的特征，以更好地了解这种药物治疗使用的内在风险。最后，通过使用药物暴露的年龄组特定人群PK变化，以及已公布的革兰氏阴性病原体对粘菌素的敏感性数据，我们将在每个年龄组进行蒙特卡罗模拟，以评估治愈所需的特定靶向药物暴露。这是为了提供足够的暴露，以实现高目标达标率，同时将不必要的高药物暴露造成的毒性降至最低。

Project I "Colistimethate Dose Optimization in Infants and Children This project is designed to determine the age-dependent changes in pharmacokinetics of colistimethate (the infused methane-sulfonated pro-drug) and colistin in pediatric patients from full term infants to adolescents. We believe that the developmental changes in drug handling of colistimethate and colistin are large enough to warrant different dosing guidelines in pediatric sub-populations. By measuring Cmax, t1/2, Vd, CL and AUC, and by using population analysis of data derived from sparse plasma sampling techniques, and assessing the covariates of age, weight, body surface area and renal function, we will successfully be able to describe the effective and safe dose required for clinical and microbiologic cure in each of the different pediatric age groups, based on exposures studied in both adults and in experimental animals. By analyzing the safety of colistimethate and colistin post-dosing, with particular attention to a wide range of renal toxicity markers, from the standard assays of urinary creatinine and albumin, to more sophisticated markers of renal injury, including transmembrane tubular protein kidney injury molecule-1 (KIM-1), beta2-microglobulin, retinal B protein, and urinary N-acetyl-beta-D-glucosaminidase (NAG). We hope to create a detailed description of the characteristics of renal injury that may occur with colistimethate and colistin, by pediatric age group, to better understand the risks inherent in the therapeutic use of this agent. Finally, by using age-group specific population PK variation in drug exposure, together with published susceptibility data for Gram-negative pathogens to colistin, we will perform Monte Carlo simulation in each age group to assess specific targeted drug exposures required for cure. This is designed to provide sufficient exposure to achieve a high target attainment rate, while minimizing toxicity from unnecessarily high drug exposure.