Pharmacometric (PM) Core

该药物计量学(PM)核心(B)支持名为“儿科抗菌药物治疗的发展和转译药理学”的计划，该计划是根据RFA-HD-10-026：儿科发展药理学(RPDP)专门研究中心(U54)的申请提交的。加州大学圣地亚哥分校拟议项目的总体主题是将发育生理学、药理学和传染病领域的非临床和临床专家聚集在一起，并进行转化性研究，以推动儿科发育药理学领域的发展。PM Core将利用加州大学圣地亚哥分校现有的PK/PD建模专业知识和流程，为所有三个项目和目前的两个试点项目提供药代动力学/药效学和疾病动力学分析支持。它将利用最先进的基于种群和生理的方法，结合药物处置的成熟模型，并最终导致改进的成熟模型。作为对这些项目的直接支持，该核心将构建氨甲环己酯和粘菌素的群体药代动力学模型，该模型包含了发育变化，并利用了血浆和尿液药物浓度。蒙特卡罗模拟将被用来帮助开发适合年龄的氨基甲酸酯剂量。PM Core还将开发内源生产模型，以应对感染并量化与药物抗生素的体外相互作用。最终，我们将把药物抗生素的长春新碱生成模型与基于生理的药代动力学(PBPK)模型联系起来 评估潜在感染部位的药物-药物相互作用。最后，药理计量学核心将开发新的氨基青霉素类药物在大鼠体内的药代动力学模型，并将目前氨基青霉素类药物在婴儿中的群体药代动力学模型扩展到年龄较大的儿童，以尿液排泄为特征。这将有助于更好地理解燕麦系统的功能发展和给药对燕麦底物的影响。PM核心将与定量药理学分析核心互动，以设定化验灵敏度要求，并将在协助培训和推广核心方面发挥关键作用。

This Pharmacometrics (PM) Core (B) supports the program entitled "Developmental and Translational Pharmacology of Pediatric Antimicrobial Therapy", submitted as an application responsive to RFA-HD-10-026: Specialized Center in Research in Pediatric Developmental Pharmacology (RPDP) Program (U54). The overall theme of the proposed program at UC San Diego is to bring together non-clinical and clinical experts in the fields of developmental physiology, pharmacology, and infectious diseases and conduct translational research to advance the field of pediatric developmental pharmacology. The PM Core will leverage existing PK/PD modeling expertise and processes at UC San Diego and support pharmacokinetic /pharmacodynamic and dynamic disease analyses for all three Projects and the current two Pilot Projects. It will utilize state-of-the-art population and physiologic based approaches that incorporate maturation models of drug disposition and will ultimately lead to Improved maturation models. In direct support of the Projects, this Core will construct population pharmacokinetic models for colistimethate and colistin that incorporate developmental changes and utilize both plasma and urine drug concentrations. Monte Carlo simulations will be employed to help develop age appropriate colistimethate dosing. The PM Core will also develop endogenous production models for cathelicidin generation in response to infection and quantify in vitro interactions with pharmaceutical antibiotics. Ultimately we will link cathelicidin generation models with physiologic-based pharmacokinetic (PBPK) models of pharmaceutical antibiotics to assess drug-drug interactions at potential infection sites. Finally the pharmacometrics core will develop new pharmacokinetic models for aminopenicillins in rats and extend current population pharmacokinetic models of aminopenicillins in infants to older children characterizing urinary excretion. This will lead to a better understanding of the functional development of the Oat system and drug dosing implications for Oat substrates. The PM Core will interact with the Quantitative Pharmacology Assay Core to set assay sensitivity requirements and will play a pivotal role in assisting the Training & Outreach Core.