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Pediatric Trials Network study results in label change for hypertension drug
May 11, 2016 – The change could affect the hundreds of children who are prescribed lisinopril after kidney transplants each year.
A study conducted by the Pediatric Trials Network (PTN) has resulted in a labelling change for a widely used drug.
Lisinopril is an angiotensin converting enzyme inhibitor that is commonly prescribed to treat high blood pressure or heart failure in adults. It is also given to children who have hypertension, including children who have undergone kidney transplants. As with many other drugs, however, there has been little research to suggest the optimal dose for pediatric transplant patients. The PTN was established to answer these types of questions about drugs given to children and adolescents.
“There is a great medical need but a small market for these types of studies,” said Daniel Benjamin, Jr., MD, MPH, PhD, the PTN’s principal investigator (pictured). “This is why the PTN was formed—to conduct the studies that no one else will.”
A study led by DCRI researcher Uptal Patel, MD, and other researchers for the PTN recently resulted in a decision by the the U.S. Food and Drug Administration (FDA) to update the label for lisinopril. In addition to Patel, the study’s authors included Howard Trachtman, MD, of New York University; Adam Frymoyer, MD, of Stanford University; Laurence Greenbaum, MD, PhD, of Emory University; Daniel Feig, MD, PhD, of the University of Alabama at Birmingham; Debbie Gipson, MD, of the University of Michigan; Bradley Warady, MD, of Children’s Mercy Hospital of Kansas City; Jens Goebel, MD, of Cincinnati Children’s Hospital; and George Schartz, MD, of the University of Rochester.
The study was a multicenter, open-label pharmacokinetic study of daily oral lisinopril in 22 children, aged 7–17 years, with stable kidney function following transplant.
The researchers found that the pharmacokinetics of lisinopril in children who underwent kidney transplant were similar to hypertensive children who did not receive kidney transplants. Lisinopril was generally well tolerated by the patients and was accompanied by a lowering of blood pressure at approved pediatric doses in the study population.
The results of the study were published in the July 2015 issue of Clinical Pharmacology & Therapeutics.
Approximately 1,200 children in the United States develop end-stage renal disease (ESRD) each year. Because kidney transplantation has become the primary method of treating ESRD for children, many of these patients will be prescribed lisinopril. As a result of the FDA’s recent decision, Benjamin noted, doctors will now have a better understanding of the correct dose.
“This has been a problem for over 60 years, and we’re only now addressing it,” he said. “With the PTN, we now a have a vehicle to make those changes.”
PTN Investigators to present abstracts at the PAS Meeting in Baltimore, April 30-May 3
Here’s a sampling of presentations with more to come:
- Platform Presentation: Sunday, May 1 at 4:15 PM–Dosing of antimicrobials in the neonatal in the NICU: Does clinical practice reflect published recommendations? M England, RG Greenberg, RH Clark, M Laughon, M Cohen-Wolkowiez, DK Benjamin Jr, and PB Smith on behalf of the Administrative Core Committee of the Best Pharmaceuticals for Children Act – Pediatric Trials Network.
- Platform Presentation: Saturday, April 30, 2016 at 8:00 AM–Use of Pediatric and Adult Midazolam Population Pharmacokinetics to Assess IM Dosing and Early Drug Exposure for Status Epilepticus. E Capparelli, K Chiswell, B Smith, D Siegel, S Weinstein, S Muchohi, M Reed, J Barrett, S de Wildt, E Jaqc-Aigrain, J Ma, T Glauser for the Pediatric Trials Network.
- Poster Presentation: Tuesday, May 3 at 7:30 AM — Using Population Pharmacokinetics and Electronic Health Records to Assess Piperacillin Safety in Infants. S Salerno, C Hornik, M Cohen-Wolkowiez, PB Smith, R Clark, and D Gonzalez on behalf of the Administrative Core Committee of the Best Pharmaceuticals for Children Act – Pediatric Trials Network.
Specialized Centers in Research in Pediatric Developmental Pharmacology (U54)
The NICHD proposes to fund a limited number of research Centers that will provide an arena for multidisciplinary interactions between basic and clinical scientists interested in establishing high-quality translational research programs in the area of pediatric developmental pharmacology. The Centers also will serve as a national resource for the education of new scientists electing to pursue careers in the conduct of translational research in high priority areas of pediatric developmental pharmacology. Finally, Center investigators will facilitate important community outreach and education efforts to increase awareness and convey the importance and implications of their research activities to the general public.
Application deadline: February 18, 2016
On January 29, the babyTAPE databse was locked.
The data collected in the babyTAPE study will be used to develop, design, and validate a weight estimation tool, similar to what is pictured, specific to infants.
The study is chaired by Dr. Susan Abdel-Rahman from Children’s Mercy Hospital in Kansas City, MO. The PTN Program is chaired by Dr. Danny Benjamin and operationalized by Katherine Berezny (Program Manager at DCRI).
Since first reported in 2008 that propranolol, a beta blocker, was effective in the treatment of Infantile Hemangiomas (IH)—a birthmark that most commonly appears as a rubbery, bright red nodule of extra blood vessels in the skin, commonly called a “strawberry”—this class of drug has been used as the first line of therapy for infants with IH. Timolol, also a beta blocker, is available in topical formulation, and increasingly used off-label for small, non-complicated IH. The popularity of timolol is likely due to its perceived safety as a topical drug. However, data on timolol efficacy, safety and pharmacokinetics are limited.
Under the protocol thought leadership of Dr. Beth Drolet, Principal Investigator, the PTN’s Timolol study will enroll 100 infants between the ages of ≥32 to <50 weeks postmenstrual age. The infants will be treated with timolol for 28 days then randomized into 2 groups. One group will continue timolol treatment while the other will be withdrawn from treatment. Both groups will remain on the study in their respective groups for up to 120 days. The study will begin to enroll in the early summer of 2016 in approximately 10 US sites, and will end in the fall of 2017. The data received from the study will be presented to the FDA to support the use of timolol for the treatment of IH.
Congratulations to the PTN Pantoprazole Study Team for closing enrollment with 41 subjects. The study goal was to enroll 40 subjects in two age groups. The dedicated team worked hard to keep the study on track and accomplish this goal.
The Pantoprazole Study will evaluate the pharmacokinetics of pantoprazole in obese children and adolescents with gastroesophageal reflux disease (GERD) following administration of an oral dose of pantoprazole.
We would like to thank you for your continued interest and past input into the Best Pharmaceuticals for Children Act (BPCA) program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH). As stakeholders in this important program, we would like to keep you abreast of current developments:
1. To date, all of our BPCA legacy studies—trials conducted prior to award of the Pediatric Trials Network (PTN) in 2010—have been completed. In September 2014, we submitted the Clinical Study Report (CSR) for the Lorazepam for Status Epilepticus study. A meeting with the FDA division was held in October, and the final CSR incorporating FDA comments was submitted in November 2014. Per FDA request, we recently submitted additional analyses and reports to the agency for a potential label change of this drug.
2. In 2014, we announced one official label change—the use of sodium nitroprusside in children for blood pressure control. This year, we have the privilege to announce the label change for meropenem for intra-abdominal infections. We anticipate that data from at least three additional studies (lithium, acyclovir, and diazepam) will be submitted to the agency by the end of 2015.
3. Between 2014 and to date in 2015, the program has submitted six additional CSRs to the agency. Five of these are PTN-led studies and include: a hydroxyurea bioequivalence study that complements the BABY HUG study; ampicillin for use in preterm neonates to treat infection; lisinopril for use in patients with renal transplant to lower blood pressure; clindamycin-dosing study in patients who are obese; and fluconazole for use in preterm neonates to treat infection. In October 2014, we also submitted a draft CSR for isotretinoin for use in treating neuroblastoma. Our hope is that these submissions will result in label changes in the near future.
4. In addition to the drug studies, the PTN and the BPCA Data Coordinating Center worked closely together to submit our first device study to the agency—the TAPE study, which was approved as of May 2015.
5. The PTN is currently conducting 7 new studies, including an innovative opportunistic study of commonly used medications that more than 1,300 children are receiving for their medical conditions. These new studies on diuretics, caffeine, pediatric opportunistic PK studies (POPs), antibiotics safety, Baby TAPE, sildenafil, and pantoprazole will improve our knowledge of how drugs are used in children.
6. Through the Pediatric Clinical Pharmacology T32 fellowship program, we continue to train new pediatric clinical pharmacologists while stimulating interdisciplinary collaboration among clinical, translational, and basic researchers in pediatric therapeutics.
We would also like for you to Save the date December 9, 2015, for our Annual BPCA Stakeholders Meeting. Held on the NIH campus in Bethesda, MD, the meeting will be conducted via webinar for all non-local attendees. You will be hearing from our logistics contractor soon with further details. We hope you can participate.
Finally, we would like to express our sincere appreciation to each of you for your interest in this important program. We look forward to working with you in the 2016 calendar year on our continuing areas of interest. Please feel free to contact me with any questions or concerns.
Perdita Taylor-Zapata, M.D.
Pediatric Medical Officer
Obstetric and Pediatric Pharmacology and Therapeutics Branch (OPPTB)
The Pediatric Trials made an appearance in the pages of the Wall Street Journal on June 8. Check out the story online: http://www.wsj.com/articles/how-much-of-a-drug-is-safe-for-preemies-1433784687.
The PTN marks another milestone as the Food and Drug Administration (FDA) has published a summary report of its pediatric study of meropenem in the Federal Register.
Meropenem is a broad-spectrum anti-microbial drug often used to treat intra-abdominal infections in infants. The purpose of the PTN study, which began in the summer of 2008, was to determine the optimal dosing regimen for meropenem in infants younger than 90 days old. Researchers were also interested in determining how safe the drug is for very young infants, especially when compared with imipenem, another broad-spectrum anti-microbial drug closely related to meropenem.
The trial included 200 infants at 24 neonatal intensive care units across the United States. Findings suggested that meropenem as dosed in the study is a safe alternative for young infants with intra-abdominal infections. The FDA recently changed the label for meropenem to reflect these findings, which were published in the Pediatric Infectious Disease Journal.
In accordance with the Public Health Service Act, the FDA is making available the labeling changes for meropenem in the Federal Register.