OVERALL PLAN ABSTRACT For our UC San Diego Research in Pediatric Developmental Pharmacology (RPDP) Center, we propose the innovative, cross-disciplinary program entitled ?Pediatric and Developmental Pharmacology for Inflammatory and Infectious Diseases?. The overall goal of the UC San Diego RPDP Center is to advance the knowledge of clinical and basic pharmacology, pharmacokinetics (PK) and clinical therapeutics of antimicrobial and anti- inflammatory agents in infants, children and adolescents. The UC San Diego RPDP brings together leading experts in pediatric clinical pharmacology, PK/pharmacodynamics (PD) computational modeling, infectious disease therapeutics, quantitative drug assay development, microbial pathogenesis, innate immunity, microbiome, metabolomics, and developmental cell biology to provide a robust, multifaceted analysis of the important and complex issues under study. Building upon an extensive track record of accomplishments in basic and clinical infectious disease and pharmacology research (former NICHD-funded Pediatric Pharmacology Research Unit for 16 years and most recently as an RPDP Center), the UC San Diego RPDP will continue to provide a robust scientific, clinical and organizational infrastructure with a highly functioning Administrative Core whose strong Clinical Pharmacology Section will support and execute the proposed Projects and highly successful Outreach and Training Section will help educate the next generation of pediatric pharmacologists. The UCSD RPDP Center will conduct non-clinical, clinical and translational studies that interconnect as they evaluate anti-inflammatory therapies and maturational changes in drug disposition, drug effects, and drug safety. Project 1 (clinical study) will evaluate the safety, PK and PD-biomarker relationships of anakinra, an anti-inflammatory IL-1 pathway blocker, in a Phase I/IIa dose escalation study in infants and children with acute Kawasaki disease and coronary artery damage. Project 2 (basic project tied to Project 1) provides a highly-innovative PD study of anti-inflammatory therapies (including anakinra) prescribed to children upon the host-microbe interactions, notably susceptibility to common pediatric infections. Project 3 will focus on understanding the functional maturation of renal drug clearance of anti-inflammatory therapies (and thus also tie into Project 1) and will develop renal organoids from human human pluripotent stem cells to characterize developmental changes in transporter markers and activity. The Pilot Project, which brings together world- renowned basic scientists with an NIH new investigator, assesses the microbiome and metabolomic changes in cystic fibrosis patients newly colonized with Pseudomonas treated with a short-course of azithromycin. Thus the UC San Diego RPDP Center will integrate highly productive basic scientists and state-of-the-art non-clinical laboratory facilities with pharmacometricians and clinician-researchers to improve our understanding of anti- inflammatory and anti-microbial therapies that are increasing in off-label use in infants and children. Ultimately, this research will lead to safer and improved therapeutics in infants and children.
The proposed research is relevant to public health because despite the broad use of anti-inflammatory and anti-microbial therapies in infants and children, there is still a gap in the proper dosing and understanding the developmental changes that impact response to therapy and susceptibility to side effects in infants and children. This Center will bring together basic scientists, pharmacologists and clinical researchers to understand these critical issues and ultimately lead to safer and improved anti-inflammatory and anti-microbial therapies in pediatrics. The proposed research is relevant to NICHD's mission by furthering the field of pediatric developmental pharmacology and by working towards ensuring that ?all children have the chance to achieve their full potential for healthy and productive lives?.
