The majority of off-patent drugs prescribed to children lack dosing information specific to this population, which can result in treatment failures and toxicities. Dosing information is lacking because clinical trials involving children pose specific challenges, among the most important of which is the large number of children required to estimate appropriate dosing at every stage of child development. Population physiologically based pharmacokinetic (PBPK) models are mathematical tools that incorporate changes of childhood, along with drug characteristics and genetic variances, to find the most appropriate dose for every pediatric age. By incorporating these factors, PBPK models can reduce the number of children needed for clinical trials. This proposal will systematically develop, and prospectively validate, population PBPK modeling in children.

Public Health Relevance

Enrolling children in clinical trials to establish the safest and most efficacious dose of commonly used drugs is challenging. This proposal will evaluate a mathematical tool, population physiologically-based pharmacokinetic models, to reduce the number of children enrolled in clinical trials without compromising the quality of dosing information.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD076676-01A1
Application #
8661919
Study Section
Special Emphasis Panel (ZRG1-EMNR-D (55))
Program Officer
Ren, Zhaoxia
Project Start
2014-08-01
Project End
2018-06-30
Budget Start
2014-08-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$621,379
Indirect Cost
$225,596
Name
Duke University
Department
Other Clinical Sciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Wang, Laura A; Cohen-Wolkowiez, Michael; Gonzalez, Daniel (2016) Advances in Pediatric Pharmacology, Therapeutics, and Toxicology. Adv Pediatr 63:227-54
Gonzalez, Daniel; Palazzi, Debra L; Bhattacharya-Mithal, Leena et al. (2016) Solithromycin Pharmacokinetics in Plasma and Dried Blood Spots and Safety in Adolescents. Antimicrob Agents Chemother 60:2572-6
Zimmerman, Kanecia; Putera, Martin; Hornik, Christoph P et al. (2016) Exposure Matching of Pediatric Anti-infective Drugs: Review of Drugs Submitted to the Food and Drug Administration for Pediatric Approval. Clin Ther 38:1995-2005
Ku, Lawrence C; Wu, Huali; Greenberg, Rachel G et al. (2016) Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine. Ther Drug Monit 38:728-737
Hill, Kevin D; Sampson, Mario R; Li, Jennifer S et al. (2016) Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects: effect of elevated hepatic pressures. Cardiol Young 26:354-62
Gonzalez, Daniel; Delmore, Paula; Bloom, Barry T et al. (2016) Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants. Antimicrob Agents Chemother 60:2888-94
Greenberg, Rachel G; Melloni, Chiara; Wu, Huali et al. (2016) Therapeutic Index Estimation of Antiepileptic Drugs: A Systematic Literature Review Approach. Clin Neuropharmacol 39:232-40
Zimmerman, Kanecia O; Wu, Huali; Greenberg, Rachel et al. (2016) Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic Modeling to Evaluate Sirolimus Drug Exposure-Response Relationships in Renal Transplant Patients. Ther Drug Monit 38:600-6
Thakkar, N; Gonzalez, D; Cohen-Wolkowiez, M et al. (2016) An opportunistic study evaluating pharmacokinetics of sildenafil for the treatment of pulmonary hypertension in infants. J Perinatol 36:744-7
Gonzalez, Daniel; Melloni, Chiara; Poindexter, Brenda B et al. (2015) Simultaneous determination of trimethoprim and sulfamethoxazole in dried plasma and urine spots. Bioanalysis 7:1137-49

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