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.
Model based approaches to describing developmental drug disposition and effects play a critical role in understanding the mechanisms of antimicrobial therapy. Linked with simulations, these models can increase the knowledge generated from the RPDP Center's Projects and help translate the results into age appropriate dosing and therapy.
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