Not suitable for children, is stated in numerous medication inserts. What the manufacturer means: We don’t know what it does to them, because we’ve only tested it on adults. In practice, doctors often prescribe this medication anyway, forced by a lack of alternatives or because they know from years of experience that it is safe. This is called ‘off-label’ prescribing, giving a medicine to a patient group other than that for which it is officially intended.
But how do you determine what dosage a child needs if it has never been studied? It’s a matter of trial and error, a bit on the gamble and a bit based on logic and practical experience. Sometimes that goes well, sometimes children get too high or too low amounts. Scientists at Radboudumc believe that this should be done better. They want to refine the dosage recommendations for off-label children’s medication on the basis of research.
Off label
While they were at home because of corona, clinical pharmacology professor Saskia de Wildt (Radboudumc) and her students delved into the evidence behind off-label children’s medication. Of all the medicines that children in the Netherlands are sometimes prescribed, about half are off-label. So far nothing new. It is striking: only 10 percent of these have been shown to work well in doses, for example in studies of academic hospitals. De Wildt: ‘The rest was at most investigated in small or less good studies.’
Tjitske van der Zanden is surprised that we as a society accept this. Together with De Wildt she is director of the Netherlands Knowledge Center for Pharmacotherapy in Children (NKFK) and a PhD student at Radboudumc. During the 20th century, stricter laws were introduced to test medication before it was launched on the market, says Van der Zanden, but children remained out of the picture for a long time. Probably based on the idea that using them as guinea pigs is unethical. “But then you can also ask yourself how ethical it is to apply something to children that has never been tested on them.” Because that’s what happens in practice. Logical too: ‘If doctors wouldn’t use any unregistered medicine, the medicine cabinet would be half empty and your children would withhold a treatment that they do need.’
Toddler dose
Since 2007, pharmaceutical companies in the EU have been obliged to also test medicines on children, but this does not apply to medicines that were already on the market. In the absence of better information, doctors use the adult dosage as a basis. For example, you assume an adult weighing 70 kilos and divide the dose for a 3.5 kilo baby by twenty. But it’s not that simple, says De Wildt. ‘The whole body of a newborn is still developing, the biological systems are not yet mature.’ The organs cannot yet properly break down and excrete medication.
Newborns therefore often have to receive a lower dose than you would estimate based on weight. So discovered colleagues of De Wildt of Erasmus MC and Leiden University some ten years ago that babies were given too much morphine during medical procedures, which entails unnecessary risks. For example, babies can stop breathing due to morphine, so they have to be on a ventilator for a few days. A lower dose provides the same pain relief with fewer risks, according to a sub-study in which De Wildt was involved.
Conversely, toddlers and preschoolers often need higher doses. ‘The smaller, the more energy you use’, explains De Wildt. ‘An elephant uses much less energy per kilogram of body weight than a mouse, and that’s how it works with humans. That is why toddlers eat relatively much more than adults.’ The child’s body digests food faster and converts medicines faster. In the early days of HIV medication, for example, doctors were amazed that young patients barely responded to the antiviral drugs until they discovered that they were giving too little. Now the recommended dose in children up to 6 years of age is higher than in older children.
Healthy kidneys
As soon as you ingest something, all kinds of organs and body cells start to interfere with that substance. There is still quite a bit to learn about the child’s body in that regard. A PhD student of De Wildt, Nori Smeets, recently discovered that there were no good values for the kidney function of newborns. Guidelines were contradictory and based on studies with few children. Smeets collected the figures from all the studies she could find and made a new calculation, showing how kidney function changes in the first month of life. If you know that, you can better estimate how quickly the kidneys process medication.
The researchers are also trying to better understand the child’s body in the laboratory. For example, they use pieces of intestinal tissue obtained with parental consent from deceased children or from operations where it would be thrown away. In the lab, they run a drug through that tissue and study what happens. They are looking, among other things, at transporters: a kind of wheelbarrow that helps a medicine in and out of cells, so that it can enter the blood through the intestinal wall. De Wildt: ‘If you know which transporters are active at which age, you can predict how quickly the drug enters the blood.’
Virtual kids
All the knowledge that De Wildt and her colleagues collect, both through their own research and (inter)national collaboration projects, are put into computer models: ‘virtual children’. Add information about a specific drug to such a virtual child and the computer calculates what the dosage should be per age group.
It may sound exciting to rely on such advice from a model, because does a real child react the same as a virtual child? In any case, De Wildt has faith in the computer models: ‘These virtual children are really getting better and better.’ In addition, those who want to wait for large patient studies can wait for some off-label medications until they weigh an ounce.