Prioritizing the Pediatric Dosage Puzzle

People often tell me that it must be incredibly sad and emotional to work in pediatrics. And though it can certainly be distressing at times, kids can be unbelievably tough and their medical journey often finishes with a happy ending. I am always impressed by their resilience and positive attitudes.

I am a Clinical Associate Professor at the Ernest Mario School of Pharmacy at Rutgers University in New Jersey and I also have a practice site at Saint Barnabas Medical Center nearby. As a pharmacist – and from the studies I have been part of, my interactions with children and parents, and my own personal experience as a mother – I think I offer an interesting perspective on the disconnect between drug companies and pediatric patients. There are a few areas that the industry needs to prioritize and improve upon when it comes to pediatric medicines.

When developing any medicine, the priority is obviously the medicine’s efficacy and safety, meaning that the actual dosage form can be an afterthought. With a growing emphasis on how patient compliance can be improved, the dosage form is receiving increasing attention, but children’s requirements are still overlooked. As an obvious example, many medicines taste bad – especially liquids. Taste may be less important in adult medication – after all, (most) adults can apply reason and overcome the obstacle – but trying to get young children to take a bitter tasting medicine can be a real struggle. The result is non-adherence – few parents want to wrestle with their child every time a dose needs to be administered.

Dosage should not be guesswork

Administering medications to children oftentimes requires manipulating the dosage form, either by crushing or splitting tablets or mixing with water or food. The manufacturers probably don’t like us modifying their medicine, but when dealing with kids that require much lower doses, we don’t really have a choice, if no appropriate medicines exist for certain age groups. And with rare diseases, pediatric medicines are even scarcer.

A child recently came into our hospital with epilepsy. To help control her condition she was on a ketogenic diet, so we had to rule out liquid dosage forms, as they are often full of carbohydrates. The remaining option was a tablet, but because of her age and weight we calculated that she’d need three quarters of a tablet. Splitting a tablet in half is hard enough, but splitting off a quarter is almost impossible because the tablet begins to crumble; we had to resort to crushing the tablet, mixing in water, then administering three quarters of that.

Liquid medications can also be challenging at low dosage. We often have infants who require volumes of 0.1mL or less, and sometimes we resort to diluting medications just to make them more measureable. Each of these manipulations that we resort to in preparing pediatric medications leads to another chance for human error and an increased risk of an adverse event. At the other end of the spectrum, I have seen lots of teenagers who have not learned to swallow pills correctly! One moment, I’ll be working with a neonate and struggling to find an appropriate drug concentration and size; the next, I’ll be tackling a 14-year old, who is refusing to take a tablet... Pediatric medicines need to come in all shapes and sizes, and we need more attention and research in the area.

Altering dosage forms to fit the patient isn’t out of the ordinary for a pharmacist, of course, but it occurs far more with medications for children. Last year, one of our pediatric pharmacy residents led a multi-center study that looked into the manipulation of dosages forms. The study found that we manipulate dosage forms three times more often in children than in adults; the study demonstrates that pediatric patients aren’t what drug makers have in mind when developing medications – despite efforts from regulators to encourage innovation.

Another relatively new factor to bear in mind is the issue of pediatric obesity, which raises the question of what exactly dosage is based on (and that goes for adults, too). For many drugs, we do not really know if the pediatric dosage is based on ideal body weight, actual body weight, size, height, or another variable. The unfortunate truth is that many pediatric dosages are just estimations, as there are very few official guidelines. 

Even when pharma manufacturers do give official guidelines for pediatric dosages, they aren’t always well thought-out. I had a seven-month old baby on an IV antibiotic at the hospital. When he went home and had to switch to an oral version, his dose was to be 8 mL of liquid three times a day, which is a lot for a baby. Couple the volume with a bad smell and taste, and you can imagine how difficult it was for the parents. I’ve also worked with a medicine that took the form of a powder packet that needed to be mixed with water. The company had clear measurements for the pediatric dosage. A portion of the water was to be taken into an oral syringe and given to the child, but the amount of water needed was too much for the child to drink in one sitting, so only part of the dose was ingested at a time. In short, it’s great to have the dosage information, but I’d really like to see that extended to a dosage form that is easy and reliable for parents to give.

Doing it for the kids

On the upside, 600 new pediatric studies have been conducted (as of August 2017) since the FDA’s pediatric legislation was introduced in the early 2000s. But there is still a long way to go before we see real change for children because it takes so long for studies to result in actual labeling changes. We can only hope that those changes will truly take into account children’s needs. On the downside, pediatric studies often don’t go below the age of 12 years, which leaves a large pediatric demographic unrepresented. In particular, neonates are very difficult to cater for.

At Rutgers, we have been working with the Catalent Applied Drug Delivery Institute to try and address some of the challenges in the area. I first met Ronak Savla, who is now scientific affairs manager at Catalent, when he was a fellow in our Rutgers Pharmaceutical Industry Fellowship Program, which is a collaboration between the School of Pharmacy at Rutgers, and multiple industry partners. Ronak and I had a good conversation about pediatric research needs, and he noticed my interest in dosage forms. Once he joined Catalent, we started talking about how we could work together; Rutgers started doing more research in the area, with a special focus on formulation and dosage form design. A grant from the Catalent Institute has allowed us to survey the work of caregivers to determine, measure and quantify the problems they have in administering medication to children, including patient acceptance, dosage form appropriateness, and easy and accurate dose measuring. I know that I have encountered many problems, but I can’t write a research report simply on my experiences. We have surveyed over 1000 caregivers to help us show the industry what is really happening. If “great” products aren’t working and aren’t great for administration, the industry needs to know about it!

The American Society of Health-System Pharmacists (ASHP) has an initiative called Standardize 4 Safety to create standardized concentrations for medicines, with the aim of improving the quality of treatment and reducing error (1). The initiative has the backing of the FDA, which has given ASHP a three-year contract to develop the standardization. They’ve already come up with a list for compounded IV medications for adults and compounded oral solutions, and in the future will be working towards standardizing IV concentrations for pediatric patients. In my experience, there is a high risk for error when compounding formulations, so I hope this will make a difference.

Another inspirational project was conducted by Shonna Yin, an associate professor in the Department of Pediatrics at NYU Langone in New York. She published a study in JAMA that examined the top over-the-counter (OTC) pediatric medicines, and found that they were wildly inconsistent in dosage directions and their measuring devices (2). Since its publication in 2010, we’ve started to see a change in the industry with OTC medicines, but I’d like to see the same change with prescription medications. Yin has also released several studies researching the healthcare literacy of parents and seeing how effective administration instructions are.

All of these initiatives are moving the field in the right direction, but – as always – there’s still so much more to do. In an ideal world, we wouldn’t have to manipulate dosage forms that were made for adults; we would have access to dosage forms that were easily manipulated and measured.

Rachel Meyers is Clinical Associate Professor in the Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, New Jersey, USA, and Pediatric Clinical Pharmacist, Saint Barnabas Medical Center, Livingston, New Jersey.