This Mentored Patient-Oriented Research Career Development application will provide for a structured environment with expert mentorship that will enable Dr. Michael Cohen-Wolkowiez to develop as an independent clinical researcher. Although antibiotics are the most commonly used medications in hospitalized infants, dosing for infants is often extrapolated from data obtained in older children and adults. Piperacillin/tazobactam and metronidazole are two antimicrobials commonly used in the nursery for which few pharmacokinetic data are available in premature infants. Dr. Cohen-Wolkowiez will use an integrative approach to investigate the pharmacokinetics and pharmacodynamics of these two agents in premature infants. This approach will include: development of a multiplex antimicrobial assay to measure drug concentrations of five antimicrobials in one ultra-low-volume infant plasma sample;application of sparse sampling methodologies;advanced population PK/PD modeling;and use of clinical opportunities to collect samples. This application will capitalize on unique opportunities provided by the Pediatric Pharmacology Research Unit-funded trial, Antimicrobial PK in High-Risk Infants (PI: Benjamin). Dr. Cohen-Wolkowiez will also have access to the resources of the Duke Clinical Research Institute and the Eshelman School of Pharmacy at UNC (Kashuba, Pollack). The mentorship team assembled is uniquely qualified, and strengths include extensive clinical research experience;internationally recognized thought leadership in trial design, research methods, pharmacology, and PK/PD modeling;and a successful history of mentorship of junior faculty. Dr. Cohen-Wolkowiez's long-term goal is to advance public health by improving antibiotic safety and dosing in infants. This K23 application will provide him with the opportunity to develop a multiplex drug assay and to master PK/PD modeling and simulation techniques in addition to refining clinical trial methodologies to maximize information gained from the limited samples available in this vulnerable population. These skills will be developed through a combination of formal didactic training in pharmacology and biostatics, as well as through mentoring from nationally recognized experts in clinical trials and pediatric pharmacology.

Public Health Relevance

Relevance Statement Invasive infections in premature infants are common and often fatal. Therefore, physicians commonly prescribe antimicrobial agents to treat suspected or confirmed infections in this population. Appropriate dosing of most antimicrobial agents in infants is unknown and information obtained from older patients often has failed to accurately predict newborn drug disposition. This application will use a novel approach to investigate the pharmacokinetics and pharmacodynamics of antimicrobial agents commonly used in infants, using an ultra-low volume multiplex assay, scavenge sampling methodologies, and advanced PK-PD modeling.

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 #
5K23HD064814-04
Application #
8514953
Study Section
Special Emphasis Panel (ZHD1-DSR-A (CM))
Program Officer
Ren, Zhaoxia
Project Start
2010-08-15
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$120,003
Indirect Cost
$8,889
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Kanesvaran, Ravindran; Watt, Kevin; Turnbull, James D et al. (2015) A Single-Arm Phase 1b Study of Everolimus and Sunitinib in Patients With Advanced Renal Cell Carcinoma. Clin Genitourin Cancer 13:319-27
Autmizguine, Julie; Cohen-Wolkowiez, Michael; Ilowite, Norman et al. (2015) Rilonacept pharmacokinetics in children with systemic juvenile idiopathic arthritis. J Clin Pharmacol 55:39-44
Tremoulet, Adriana; Le, Jennifer; Poindexter, Brenda et al. (2014) Characterization of the population pharmacokinetics of ampicillin in neonates using an opportunistic study design. Antimicrob Agents Chemother 58:3013-20
Tunks, Robert D; Barker, Piers C A; Benjamin Jr, Daniel K et al. (2014) Sildenafil exposure and hemodynamic effect after Fontan surgery. Pediatr Crit Care Med 15:28-34
Hester, Willie; Fry, Caitlyn; Gonzalez, Daniel et al. (2014) Thromboprophylaxis with fondaparinux in high-risk postoperative patients with renal insufficiency. Thromb Res 133:629-33
Beam, Kristyn S; Laughon, Matthew M; Hornik, Christoph P et al. (2014) Predictors of positive cerebrospinal fluid cultures in infants with bacteremia. Pediatr Infect Dis J 33:360-5
Gostelow, Martyn; Gonzalez, Daniel; Smith, P Brian et al. (2014) Pharmacokinetics and safety of recently approved drugs used to treat methicillin-resistant Staphylococcus aureus infections in infants, children and adults. Expert Rev Clin Pharmacol 7:327-40
Laughon, Matthew M; Avant, Debbie; Tripathi, Nidhi et al. (2014) Drug labeling and exposure in neonates. JAMA Pediatr 168:130-6
Autmizguine, Julie; Guptill, Jeffrey T; Cohen-Wolkowiez, Michael et al. (2014) Pharmacokinetics and pharmacodynamics of antifungals in children: clinical implications. Drugs 74:891-909

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