Colistimethate Dose Optimization in Infants and Children

项目I“婴儿和儿童多粘菌素E甲磺酸盐剂量优化 本项目旨在确定从足月婴儿到青少年的儿科患者中多粘菌素E甲磺酸酯（输注的甲烷磺化前药）和多粘菌素的药代动力学的年龄依赖性变化。我们认为，多粘菌素E甲磺酸盐和多粘菌素的药物处理的发展变化足够大，足以保证儿科亚群的不同给药指南。通过测量Cmax、t1/2、Vd、CL和AUC，并通过使用稀疏血浆采样技术获得的数据的群体分析，以及评估年龄、体重、体表面积和肾功能的协变量，我们将能够成功描述每个不同儿科年龄组中临床和微生物学治愈所需的有效和安全剂量，基于对成人和实验动物的暴露研究。通过分析多粘菌素E甲磺酸盐和多粘菌素给药后的安全性，特别关注广泛的肾毒性标志物，从尿肌酐和白蛋白的标准测定到更复杂的肾损伤标志物，包括跨膜肾小管蛋白肾损伤分子-1（KIM-1）、β 2-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多粘菌素E甲磺酸盐和多粘菌素可能发生的肾损伤特征，以更好地了解该药物治疗用途的固有风险。最后，通过使用药物暴露的年龄组特定人群PK变化，以及已发表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中进行Monte Carlo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，以实现高的目标实现率，同时最大限度地减少不必要的高药物暴露的毒性。

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.