WHY Pediatric PH Research is Needed

Dr. Ivy (far right) treats a young PH patientDr. Ivy (far right) treats a young PH patient

“It is believed that in the United States, pulmonary arterial hypertension (PAH) will affect 40-50 pediatric patients per million children at some point in their lives.” While research has come incredibly far in the last 15 years or so, with twelve approved PH therapies and many more in the pipeline, none of these therapies is approved for use in children.

You may think this is not a problem. We can just treat children like “small adults,” with smaller medicaton doses, right?

Unfortunately, the answer is no. Children are not just “small adults.” I sat down with two leading pediatric PH specialists to find out more. Thanks to Robyn Barst, MD, and Dunbar Ivy, MD, for their contributions to this article.

Why is it important to consider pediatric patients separately from the adult PH population?

In short, Dr. Ivy says that the disease is often different. While there are some idiopathic PAH patients in the pediatric population, there are also many who have conditions not so commonly found in adults, such as lung disease of prematurity and congenital heart disease.

In addition, the metabolism of children is vastly different from that of adults. And while it stands to reason that the dosing is therefore different, it doesn’t necessarily mean just giving an arbitrary “less.” Sometimes children metabolize drugs more rapidly and need higher doses, while other times their liver is not well developed and they should receive less medication. If the metabolic pathway is not maturely developed, some medications may have serious consequences. Further, a child’s metabolism can change throughout childhood, and even for children who have “normal” metabolism for their age, metabolism changes from toddlers to adolescents. Therefore, dosing based on weight can also be affected by age.

Dr. Barst says that when it comes to a treatment like Flolan®, for instance, it has been found that a higher dose per body weight is actually more effective than in adult patients. It took a long time for practitioners to realize this, but when they tried to cut back on high doses, kids actually got worse.

While it is true that pediatric patients likely metabolize medication more quickly (and thus may require more frequent dosing), in very young infants the metabolism of medication may in fact be much slower and too much medication too often can cause organ dysfunction in tiny bodies.

These dosing questions should not be trial and error, and clinical trials and pediatric guidelines would help with more targeted dosing recommendations.

Dr. Barst says pediatric practitioners are now seeing that there may be an optimal window of development, a time when more aggressive treatment may in fact have a higher impact on outcome, largely due to the growth and change in the body during childhood. More research on what that window of development is, and how to best capitalize on it, is also needed.

What personal traits do kids bring to the table that makes them different to treat?

When it comes to the basics of administering and tracking treatments, kids bring their own set of challenges, often in the following areas:

Medication: Often, the delivery of the dose can be problematic. As of this publication, four PH medications come in pill form and two are inhaled (note: there are now seven PH medications in pill form and two inhaled medications). Both may be challenging for small children. As Dr. Ivy explains, a medication that can be delivered in liquid suspension and easily swallowed is often important, even ideal, and some PH medications do not translate well into that form. Three medications are delivered continuously via IV 24 hours a day, and this can be very tricky for an active child of any age. Likewise, keeping oxygen on a child on the move can be very difficult.

Outcomes: While an adult PH patient with advanced disease is likely very symptomatic, the same does not necessarily hold true for the pediatric patient unless they are very sick. A six-minute walk, the standard evaluation for PH function and class in adults, does not work as well with a pediatric patient. It can, in fact, be invalid because even children with advanced PH may still have good heart function. Since the six-minute walk is also a primary endpoint in clinical trials and is often used to gauge how effective a course of treatment is, different standards need to be developed for pediatric patients.

Social Factors: Most people don’t really like to be different, but in kids this can be even more true. Dr. Ivy explains that it is a challenge to convince a small child to carry a backpack or wear oxygen all the time when it makes them feel like they stand out and are different from their friends. Developmentally, children rely on social interactions and understanding from their peers a great deal, and we must take steps to support this process in a way that both allows them to grow socially and addresses their medical needs.

In closing, both doctors envision a world where they can treat pediatric patients with more effective medications: medications that are easy to administer, have minimal side effects, and are dosed or even created especially for children. As Dr. Barst stresses, this will only come with increased collaboration between researchers, doctors, pharmaceutical companies and the regulators (FDA). And we cannot forget about safety — both long-term and short-term. Most of the drugs we would treat children with will continue to be used for years, if not an entire lifetime. Knowing the effects of drugs long-term, especially in children who are continuing to grow and develop, is critical.

To that end, the Robyn Barst Pediatric Research and Mentoring Fund for Pulmonary Hypertension has been established to raise funding and establish mentoring programs for promising pediatric researchers and practitioners.

This article first appeared in Pathlight, Summer 2012.

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