This Mentored Patient-Oriented Research Career Development Award proposal will provide the ideal environment, expert mentorship, and practical and didactic training designed to facilitate Dr. Daniel Gonzalez's development as an independent clinical researcher. Dr. Gonzalez's overarching career goal is to advance public health by integrating mechanistic modeling and physiology concepts to promote safe and effective use of medications in children. Invasive infections due to antibiotic resistant bacteria are common and deadly. Unfortunately, in the last 10 years only 3 new antibiotics have been approved by the FDA in adults and none in children. Furthermore, once adult approval is obtained, often there is a substantial delay before an antibiotic is indicated for use in children. Innovative tools designed to expedite pediatric approval of novel antibiotics are needed. Physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) models are mathematical constructs that incorporate physiologic changes from childhood to adulthood. By incorporating these physiologic changes, PBPK/PD models can be used to design pediatric clinical trials using adult data, and, thus, reduce the time to antibiotic approval in children. However, PBPK/PD models have not been applied consistently in drug development largely due to a lack of prospective model validation. In this proposal Dr. Gonzalez will evaluate a platform to systematically develop and prospectively validate PBPK/PD models in adults and children for a novel antibiotic in development. He hypothesizes that the developed PBPK/PD models will provide a mechanistic understanding of the factors affecting drug exposure at the site of infection for a new antibiotic, aid in selection of optimal dosing in adults and children, and serv as a model for future antibiotic drug approvals. The candidate is a recent graduate of the UNC/Duke T32 Collaborative Clinical Pharmacology training program, through which he acquired training in pediatric clinical pharmacology. The candidate's short term goals for the K23 program are: 1) to acquire knowledge and skills in PBPK/PD modeling and simulation; 2) to develop the professional skills to successfully lead a clinical trial research team; and 3) to generate a critical mass of preliminary data and publications to support an R01 grant application important for Dr. Gonzalez's development as an independent clinical researcher. This proposal capitalizes on a long history of collaboration between Duke University and University of North Carolina at Chapel Hill as well as data already available to complete the proposed research. The mentorship team has a track record of successful mentorship of junior faculty and has internationally recognized expertise in pediatric clinical trials, clinical pharmacology, PBPK/PD modeling, and infectious diseases. Upon successful completion of this proposal, Dr. Gonzalez will have acquired the necessary skillset to pursue a lifelong career in promoting safe and effective use of drugs in children.

Public Health Relevance

Antibiotics are frequently prescribed in the pediatric population due to invasive infections; however, despite rising antibiotic resistance rates, there i a lack of novel antibiotics in clinical development. Once adult approval is obtained for a new antibiotic, there is often a lag time before a product is indicated for pediatric use. This proposa will investigate a novel approach to evaluate the utility of physiologically-based pharmacokinetic (PK)/pharmacodynamic (PD) models in shortening the lag time of antibiotic approvals in children.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HD083465-02
Application #
9053303
Study Section
Biobehavioral and Behavioral Sciences Subcommittee (CHHD)
Program Officer
Zajicek, Anne
Project Start
2015-04-15
Project End
2020-02-29
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Duan, Peng; Wu, Fang; Moore, Jason N et al. (2018) Assessing CYP2C19 Ontogeny in Neonates and Infants Using Physiologically Based Pharmacokinetic Models: Impact of Enzyme Maturation Versus Inhibition. CPT Pharmacometrics Syst Pharmacol :
Ku, Lawrence C; Hornik, Christoph P; Beechinor, Ryan J et al. (2018) Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus. CPT Pharmacometrics Syst Pharmacol 7:718-727
Maharaj, Anil R; Gonzalez, Daniel; Cohen-Wolkowiez, Michael et al. (2018) Improving Pediatric Protein Binding Estimates: An Evaluation of ?1-Acid Glycoprotein Maturation in Healthy and Infected Subjects. Clin Pharmacokinet 57:577-589
Autmizguine, Julie; Melloni, Chiara; Hornik, Christoph P et al. (2018) Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children. Antimicrob Agents Chemother 62:
Sherwin, Jennifer; Thompson, Elizabeth; Hill, Kevin D et al. (2018) Clinical pharmacology considerations for children supported with ventricular assist devices. Cardiol Young 28:1082-1090
Salerno, Sara N; Burckart, Gilbert J; Huang, Shiew-Mei et al. (2018) Pediatric Drug-Drug Interaction Studies: Barriers and Opportunities. Clin Pharmacol Ther :
Gonzalez, Daniel; James, Laura P; Al-Uzri, Amira et al. (2018) Population Pharmacokinetics and Safety of Solithromycin following Intravenous and Oral Administration in Infants, Children, and Adolescents. Antimicrob Agents Chemother 62:
Puia-Dumitrescu, Mihai; Bretzius, Olivia M; Brown, Nia et al. (2018) Evaluation of Gentamicin Exposure in the Neonatal Intensive Care Unit and Hearing Function at Discharge. J Pediatr 203:131-136
Ge, Shufan; Beechinor, Ryan J; Hornik, Christoph P et al. (2018) External Evaluation of a Gentamicin Infant Population Pharmacokinetic Model Using Data from a National Electronic Health Record Database. Antimicrob Agents Chemother 62:
Hornik, Christoph P; Gonzalez, Daniel; van den Anker, John et al. (2018) Population Pharmacokinetics of Intramuscular and Intravenous Ketamine in Children. J Clin Pharmacol :

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