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.

POPS Paradigm Explained

PTN studies managed via the POPS paradigm seek to determine the appropriate dosing of understudied drugs in children by using samples collected as part of regular care (for example, blood draws). The data collected provides valuable pharmacokinetic and dosing information for drugs in different pediatric age groups and special pediatric populations (such as obese children).

Dr. Ram Yogev, POPS Investigator at Lurie Children’s Hospital of Chicago, explains, “The current empirically-based dose selection for pediatric patients can be improved by applying evidence-based dosing strategies. POPS studies provide important information about how best to dose medications in children and adolescents, and support dosing strategies that provide the best chance for any given drug to demonstrate both efficacy and acceptable tolerability.”

Since its inception, POPS has investigated 48 understudied drugs with 19 currently enrolling. POPS has a total of 31 active sites, and in March, two UK sites joined the ranks, Southampton General Hospital and Alder Hey Children’s Hospital. As of June 1, POPS sites enrolled 1904 participants of the targeted 3000.

A POPS site goes above and beyond

The Lurie Children’s team (from left to right): Rohit Kalra, Brize Morales, Ram Yogev, Laura Fearn, Kathy Rosa, and Mayra Gomez
The Lurie Children’s team (from left to right): Rohit Kalra, Brize Morales, Ram Yogev, Laura Fearn, Kathy Rosa, and Mayra Gomez

For an example of an outstanding PTN site, look no further than Ann & Robert H. Lurie Children’s Hospital of Chicago. The top enrolling site for the POPS study, Lurie Children’s has enrolled 244 patients as of September 22. To put this number into perspective, the second highest enrolling POPS site has recruited 117 patients, and the third highest 99 patients. Lurie Children’s is also a leader in the clindamycin trial, enrolling almost one third of the patients needed to complete the study. A nimble team of 6 individuals makes it all happen, under the direction of Dr. Ram Yogev, site PI and professor in Pediatrics–Infectious Diseases at Northwestern University Feinberg School of Medicine.

Dr. Yogev attributes his site’s success to communication and dedication. Site team members participate in a mandatory weekly meeting to review study progress over the preceding week and to identify and troubleshoot any problems that may have arisen. This combination of accountability and collaboration helps to ensure that everyone keeps invested in the team’s success.

But, Dr. Yogev is careful to note, communication must extend beyond the confines of the site team to ensure optimal conduct of a study. To this end, he devotes a great deal of time nurturing relationships in other departments at his institution to facilitate understanding of study goals and to bank good will with people who can help make reaching those goals possible. Dr. Yogev observes, “You can’t rely on the hierarchy to make things happen; it’s personal relationships that create a willingness to help.”

For example, one study of a drug with a very short half-life required sampling at 3 time points within a half hour. To ensure coverage for those draws, non-study personnel in relevant departments had to be enlisted and reminded to alert the site team of when eligible patients would be available. Such teamwork would be difficult to foster had those individuals not been approached and befriended by Dr. Yogev. “Thanks to this study, I have more friends than I had before,” he jests.

Much of what drives Dr. Yogev to go the extra mile in this regard is the desire to be an example to his team. “If your people see that you are dedicated,” he observes, “they will try to match or even beat that dedication.” In fact, he admits that he is in friendly competition with his study coordinator, Laura Fearn, to be the best at what they do (and she usually wins, he notes). Other team members who routinely go above and beyond include Jannie Stewart (site phlebotomist), Kathy Rosa (regulatory specialist), and Mayra Gomez (data entry coordinator).

When asked about why he decided to become involved with the Pediatric Trial Network, Dr. Yogev highlights the critical lack of knowledge to inform dosing of the vast majority of drugs used in kids. Collaboration between government, academia, and industry, he notes, is a positive way to make crucial changes — “I only wish I had come up with the idea myself!”

The POPS study grows by leaps and bounds

The POPS study is moving full steam ahead. In September 2012, the study received additional funding from the National Institute of Child Health and Human Development to effectively double in size, increasing the number of patients enrolled from 500 to ~1000 and doubling the number of participating sites from ~15 to ~30.

And the new year has brought new momentum. In January, the study added 7 new drugs of interest to the 12 already being studied. To date, 375 patients are enrolled, and recruitment will continue into 2014 unless the targeted enrollment is met sooner. Analysis of one drug of interest – ampicillin – is already underway.

POPS (Pharmacokinetics of Understudied Drugs Administered to Children per Standard of Care) is designed to characterize the pharmacokinetics of drugs that lack specific dosing recommendations and safety data in children. Many drugs prescribed in the United States lack such information for kids, and, unfortunately, these knowledge gaps place young people at risk for adverse events and therapeutic failure.

In POPS, the drugs of interest are being administered to children by their treating physicians according to local standards of care. The only study procedure involves biological sample collection during the time of drug administration. Participants are followed for up to 90 days. To find out whether there’s a participating site near you, visit