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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD071600-04
Application #
8677919
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Lam, Lisa H; Capparelli, Edmund V; Kurzrock, Razelle (2016) Association of concurrent acid-suppression therapy with survival outcomes and adverse event incidence in oncology patients receiving erlotinib. Cancer Chemother Pharmacol 78:427-32
Le, J; Dam, Q; Schweizer, M et al. (2016) Effects of vancomycin versus nafcillin in enhancing killing of methicillin-susceptible Staphylococcus aureus causing bacteremia by human cathelicidin LL-37. Eur J Clin Microbiol Infect Dis 35:1441-7
Martovetsky, Gleb; Bush, Kevin T; Nigam, Sanjay K (2016) Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers. Drug Metab Dispos 44:1050-60
Shoji, Kensuke; Bradley, John S; Reed, Michael D et al. (2016) Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms. Antimicrob Agents Chemother 60:2150-6
Sakoulas, George; Olson, Joshua; Yim, Juwon et al. (2016) Cefazolin and Ertapenem: A Synergistic Combination Used to Clear Persistent Staphylococcus aureus Bacteremia. Antimicrob Agents Chemother :
Lin, Leo; Kim, Janie; Chen, Hope et al. (2016) Component Analysis of Multipurpose Contact Lens Solutions To Enhance Activity against Pseudomonas aeruginosa and Staphylococcus aureus. Antimicrob Agents Chemother 60:4259-63
Hollands, Andrew; Corriden, Ross; Gysler, Gabriela et al. (2016) Natural Product Anacardic Acid from Cashew Nut Shells Stimulates Neutrophil Extracellular Trap Production and Bactericidal Activity. J Biol Chem 291:13964-73
Cole, Jason N; Nizet, Victor (2016) Bacterial Evasion of Host Antimicrobial Peptide Defenses. Microbiol Spectr 4:
Kumaraswamy, Monika; Lin, Leo; Olson, Joshua et al. (2016) Standard susceptibility testing overlooks potent azithromycin activity and cationic peptide synergy against MDR Stenotrophomonas maltophilia. J Antimicrob Chemother 71:1264-9
Bosi, Emanuele; Monk, Jonathan M; Aziz, Ramy K et al. (2016) Comparative genome-scale modelling of Staphylococcus aureus strains identifies strain-specific metabolic capabilities linked to pathogenicity. Proc Natl Acad Sci U S A 113:E3801-9

Showing the most recent 10 out of 61 publications