Pharmacometric (PM) Core

本药理学（PM）核心（B）支持题为“儿科抗菌治疗的发展和转化药理学”的项目，该项目作为响应RFA-HD-10-026的申请提交：儿科发育药理学（RPDP）项目（U 54）研究专门中心。在加州大学圣地亚哥分校拟议计划的总体主题是汇集发育生理学，药理学和传染病领域的非临床和临床专家，并进行转化研究，以推进儿科发育药理学领域。 PM Core将利用UC San Diego现有的PK/PD建模专业知识和流程，并支持所有三个项目和当前两个试点项目的药代动力学/药效学和动力学疾病分析。它将利用最先进的人口和生理为基础的方法，结合成熟模型的药物处置，并最终导致改进的成熟模型。为直接支持项目，该核心将构建多粘菌素E甲磺酸盐和粘菌素的群体药代动力学模型，该模型将纳入发育变化并利用血浆和尿液药物浓度。 将采用Monte Carlo模拟来帮助开发适合年龄的多粘菌素E甲磺酸盐给药。PM Core还将开发针对感染的cathelicidin生成的内源性生产模型，并量化与药物抗生素的体外相互作用。最终，我们将cathelicidin生成模型与药物抗生素的生理药代动力学（PBPK）模型联系起来， 评估潜在感染部位的药物相互作用。最后，药物计量学核心将开发新的大鼠氨基青霉素药代动力学模型，并将目前的婴儿氨基青霉素群体药代动力学模型扩展到年龄较大的儿童，以表征尿排泄。这将导致更好地了解燕麦系统的功能发展和药物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，以设定分析灵敏度要求，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.