Systemic Timolol Exposure Following Topical Application to Infantile Hemangiomas

Journal of the American Academy of Dermatology • February 2019.

Drolet BA, Boakye-Agyeman F, Harper B, Holland K, Lewandowski A, Stefanko N, Melloni C; Pediatric Trials Network Steering Committee.

Off-label ophthalmic timolol has been rapidly adopted for treatment of infantile hemangioma since topical application of beta-blockers was presumed to have an improved safety profile compared to oral administration. We examined timolol plasma concentrations in children receiving ophthalmic preparations applied to skin hemangiomas.

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A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data

Journal of Pharmacokinetics and Pharmacodynamics • June 2018.

Dallefeld SH, Atz AM, Yogev R, Sullivan JE, Al-Uzri A, Mendley SR, Laughon M, Hornik CP, Melloni C, Harper B, Lewandowski A, Mitchell J, Wu H, Green TP, Cohen-Wolkowiez M.

Amiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature.

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Population Pharmacokinetics of Intramuscular and Intravenous Ketamine in Children

The Journal of Clinical Pharmacology • April 2018.

Hornik CP, Gonzalez D, van den Anker J, Atz AM, Yogev R, Poindexter BB, Ng KC, Delmore P, Harper BL, Melloni C, Lewandowski A, Gelber C, Cohen-Wolkowiez M, Lee JH; Pediatric Trial Network Steering Committee.

Ketamine is an N-methyl D-aspartate receptor antagonist used off-label to facilitate dissociative anesthesia in children undergoing invasive procedures. Available for both intravenous and intramuscular administration, ketamine is commonly used when vascular access is limited. Pharmacokinetic (PK) data in children are sparse, and the bioavailability of intramuscular ketamine in children is unknown.

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PTN welcomes first sites in Australia

The Pediatric Trials Network (PTN) welcomed its first two Australian sites in February. Sydney Children’s Hospitals Network and the Royal Children’s Hospital in Melbourne are now participating in PTN’s Pharmacokinetics of Understudied Drugs in Infants and Children (POPS) study.

The sites are currently involved in the Paediatric Trials Network Australia (PTNA), a counterpart of PTN that brings together pediatric researchers from across Australia who are committed to improving child health through the facilitation of pediatric clinical trials.

“These sites bring considerable experience in pediatric research and will make a significant contribution to PTN’s work,” said Dr. Danny Benjamin, principal investigator for the PTN. “In addition, their involvement will expand PTN’s global footprint, allowing us to gather data from a more diverse and widespread group of children and infants that can better inform our research.”

The POPS study is designed to assess the pharmacokinetics of a variety of commonly used drugs in children and infants that have limited safety and dosing information in the pediatric population. More than 70 drugs used to treat nearly 50 diseases and conditions have been studied so far.

Sydney Children’s Hospital, Randwick
Kids Research Institute, Westmead
Royal Children’s Hospital, Melbourne

15 IDeA sites welcomed into PTN POPS study

Fifteen sites in states participating in the NIH Institutional Development Award (IDeA) program are being onboarded into the Pediatric Trials Network’s (PTN) POPS study of commonly used medications in children.

The IDeA program aims to build research capacities in states that have historically received low levels of NIH funding by supporting research, faculty development, and infrastructure improvements. The IDeA States Pediatric Clinical Trial Network (ISPCTN), a network of IDeA sites established by the NIH’s Environmental Influences on Child Health Outcomes (ECHO) Program, recruits study participants from states whose populations are disproportionately rural and medically underserved.

“Historically, these populations have been underrepresented in multicenter clinical trials and their involvement in this study will provide them an opportunity to participate in clinical research,” said Jeannette Y. Lee, principal investigator for the ISPCTN and Professor of Biostatistics at the University of Arkansas for Medical Sciences. “PTN will also provide the sites with a way of interacting with a large community of clinical trial researchers and a venue for contributing to clinical research.”​

The Pharmacokinetics of Understudied Drugs Administered to Children Per Standard of Care (POPS) study is designed to better characterize the pharmacokinetics of a variety of commonly used drugs in children and infants for which limited information is available in the pediatric population. More than 70 drugs (36 currently enrolling) used to treat nearly 50 diseases and conditions have been studied so far.

“We are excited to welcome these sites, and feel confident that they will make a vital contribution to the POPS study,” said Dr. Chiara Melloni, co-investigator of the study and Assistant Professor of Medicine at Duke University. “Their participation will allow PTN to expand enrollment and ensure that a more diverse and inclusive population of children is represented in this important study.”

The 15 new study sites are:

  • Alaska Native Medical Center in Anchorage, Alaska
  • Kapiolani Medical Center for Women and Children in Honolulu, Hawaii
  • University of Kansas Medical Center in Kansas City, Kansas
  • Tulane University Health Science Center in New Orleans, Louisiana
  • University of Mississippi Medical Center in Jackson, Mississippi
  • Children’s Mercy Hospitals and Clinics in Kansas City, Missouri
  • University of Montana in Missoula, Montana
  • Dartmouth-Hitchcock Medical Center in Dartmouth, New Hampshire
  • University of New Mexico Health Sciences Center in Albuquerque, New Mexico
  • University of Nebraska Medical Center in Omaha, Nebraska
  • Board of Regents of the University of Oklahoma in Oklahoma City, Oklahoma
  • Rhode Island Hospital in Providence, Rhode Island
  • University of Vermont Medical Center in Burlington, Vermont
  • University of South Carolina in Columbia, South Carolina
  • West Virginia University Hospital in Morgantown, West Virginia

Four IDeA sites are already participating in the study: the Arkansas Children’s Research Institute in Little Rock, Arkansas; the Alfred I. DuPont Hospital for Children in Wilmington, Delaware; the University of Louisville Norton Children’s Hospital in Louisville, Kentucky; and the Medical University of South Carolina Children’s Hospital in Charleston, South Carolina.

Comparative Analysis of Ampicillin Plasma and Dried Blood Spot Pharmacokinetics in Neonates

Therapeutic Drug Monitoring • February 2018.

Le J, Poindexter B, Sullivan JE, Laughon M, Delmore P, Blackford M, Yogev R, James LP, Melloni C, Harper B, Mitchell J, Benjamin DK Jr, Boakye-Agyeman F, Cohen-Wolkowiez M.

Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated. An open-label, multicenter, opportunistic, prospective study was conducted in neonates.

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Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children

Antimicrobial Agents and Chemotherapy • December 2017.

Autmizguine J, Melloni C, Hornik CP, Dallefeld S, Harper B, Yogev R, Sullivan JE, Atz AM, Al-Uzri A, Mendley S, Poindexter B, Mitchell J, Lewandowski A, Delmore P, Cohen-Wolkowiez M, Gonzalez D; the Pediatric Trials Network Steering Committee.

Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii infections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children.

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PTN determines appropriate TMP/SMX dosing in infants and children

Micky Cohen-Wolkowiez, MD, PhD
Micky Cohen-Wolkowiez, MD, PhD

The Pediatric Trials Network (PTN), with funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), recently completed a multicenter study of trimethoprim/sulfamethoxazole (TMP/SMX) to determine appropriate dosing for infants and children. The results of the study were published in the journal Antimicrobial Agents and Chemotherapy on Oct. 30.

TMP/SMX is a combination antibiotic used to treat various types of bacterial infections in children, including urinary tract infections, bacterial pneumonia, and skin abscesses caused by methicillin-resistant Staphylococcus aureus (MRSA). Although it is one of the most commonly used drugs for treating infections in infants and children, pharmacokinetic data in children are lacking and appropriate dosing information had never been determined for this population.

“It’s common to extrapolate adult doses to treat children,” said Dr. Michael (Micky) Cohen-Wolkowiez, co-principal investigator for the study. “However, developmental changes during childhood play a significant role in drug dosing, and failure to account for these changes often leads to decreased drug efficacy and safety in young patients.”

During the study, investigators analyzed samples from 153 infants and children who had been given TMP/SMX as part of their treatment. The TMP/SMX combination is one of more than 30 drug therapies given as part of standard care that are being evaluated in POPS, a study that began in 2011 and is expected to have enrolled approximately 3000 patients by 2018.

Only a small percentage of drugs and devices approved by the FDA are actually labeled for pediatric use. As a result, pediatricians must frequently prescribe medical therapies according to their best guess based on dosing information from adult studies.

PTN, a network of more than 100 sites in 5 countries, aims to fill this gap by conducting trials primarily with off-patent drugs that lack data to guide their use in pediatric populations. Since its inception in 2011, it has studied 72 drugs to determine appropriate dosing for children and infants.

Respiratory Support for Very Low Birth Weight Infants Receiving Dexamethasone

The Journal of Pediatrics • April 2017.

Virkud YV, Hornik CP, Benjamin DK, Laughon MM, Clark RH, Greenberg RG, Smith PB.

To assess how neonatal intensive care units followed the American Academy of Pediatrics guidelines for use of dexamethasone in preterm infants by evaluating respiratory support at the time of dexamethasone administration. This is an observational study of infants discharged from one of 290 neonatal intensive care units from 2003 to 2010. The cohort included very low birth weight (<1500 g birth weight) infants born at ≤32 weeks gestational age. The main outcome was respiratory support at time of exposure to dexamethasone.

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Pharmacokinetics of Clindamycin in Obese and Nonobese Children

Antimicrobial Agents and Chemotherapy • March 2017.

Smith MJ, Gonzalez D, Goldman JL, Yogev R, Sullivan JE, Reed MD, Anand R, Martz K, Berezny K, Benjamin DK Jr, Smith PB, Cohen-Wolkowiez M, Watt K; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee.

Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size.

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