Pharmacometric (PM) Core

该药物计量学（PM）核心(B)支持题为“儿科抗菌药物治疗的发展和转化药理学”的项目，作为响应RFA-HD-10-026的申请提交：儿科发展药理学研究专业中心（RPDP）项目（U54）。加州大学圣地亚哥分校拟议项目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，支持所有三个项目和当前两个试点项目的药代动力学/药效学和动态疾病分析。它将利用最先进的人口和基于生理学的方法，结合药物处置的成熟模型，并最终导致改进的成熟模型。为了直接支持该项目，该核心将构建大肠杆菌酸酯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。蒙特卡罗模拟将被用来帮助开发适合年龄的colistimethate剂量。PM Core还将开发应对感染的抗菌肽内源性生产模型，并量化与药物抗生素的体外相互作用。最终，我们将把抗菌药物生成模型与基于生理的药代动力学（PBPK）模型联系起来

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.