UNC and Duke Researchers Collaborate to Predict Drug Safety in Preemies

Children are not simply little adults. Not only do they not behave like adults, but their bodies are vastly different, with more bones, thinner skin, and narrower airways. And because of their faster metabolisms and smaller blood volumes, children often process drugs differently than grown-ups. These differences are particularly striking with premature infants, whose tiny physiques are even more susceptible to adverse reactions. Yet most of the drugs prescribed today for children and preemies have not been tested in those populations.

A research team from UNC and Duke has received a $50,000 grant to develop a new method for predicting drug safety in pediatric patients. The award is part of an effort by the neighboring CTSAs to promote collaborations that translate scientific discoveries into advances in patient care.

Daniel Gonzalez, PharmD, PhD, an assistant professor in the UNC Eshelman School of Pharmacy and Christoph Hornik, MD, MPH, an assistant professor in the Duke School of Medicine, will combine their expertise in pharmaceutical sciences and pediatrics to address the lack of good data on the potential harms associated with certain medications in premature babies.

“Doctors do their best to treat preemies with a combination of drugs, phototherapy, and other procedures as needed. Because of the lack of studies and trials in preemies, they frequently have to rely on information extrapolated from older children or even adults, or on their previous experiences,” said Hornik.

Take sildenafil, a drug commonly used to treat a serious lung condition called pulmonary hypertension that affects one in 12 extremely premature infants. Myriad studies have shown that sildenafil is safe and effective in adults with this type of high blood pressure, but safety data in premature infants are virtually non-existent. Despite the lack of evidence, Hornik found that the use of this drug in the neonatal intensive care unit increased by greater than 1000 percent between the years 2005 and 2010.

Both UNC and Duke are sites for a small clinical trial of sildenafil in 40 premature infants. Gonzalez has taken data from this trial to model the pharmacokinetics of sildenafil, or how the disposition of the drug throughout the body changes over time. His modeling takes into account factors that could explain differences in pharmacokinetics between one baby and another -- variables like age, weight, gender, and ethnicity -- to try to come up with the most accurate picture possible of how sildenafil is processed in preemies.

Gonzalez and Hornik now plan to take the extensive clinical data contained within a large database of pediatric electronic medical records and plug it into their phamacokinetic model. The Pediatrix EMR includes dosing and safety information from over 950,000 infants, representing more than a fifth of the preemies seen in NICUs throughout the United States. The researchers hope to infer how the adverse events recorded in the database are related to doses of the drug given to specific patients.

“If we are successful, our work has the potential to impact not only clinical practice, but also the design of future trials,” said Gonzalez. “This same method could eventually be expanded to assess the safety of other frequently used drugs and improve drug development efforts in premature infants.”

Though Gonzalez and Hornik have not previously collaborated, their parent institutions have an extensive infrastructure and a long history of collaboration in pediatric drug development research. Since 2001, the UNC and Duke research teams have been awarded 10 collaborative NIH grants, 8 collaborative DHHS contracts, and published more than 70 manuscripts using the Pediatrix EMR.

The new team of Gonzalez and Hornik are one of four to recently receive collaborative grants from the North Carolina Translational and Clinical Sciences (NC TraCS) Institute and the Duke University Translational Medicine Institute (DTMI). The awards place particular emphasis on basic research in a variety of disciplines that address the development of therapies, diagnostics or devices applicable to human disease and clinical trials.

UNC and Duke are the only two academic institutions in North Carolina that are members of the CTSA program, a consortium created to improve the way biomedical research is conducted across the country. The CTSA program is funded by the National Center for Advancing Translational Sciences (NCATS), a part of the National Institutes of Health (NIH).