Prescription Drug Concept

Los científicos identifican numerosos efectos secundarios nuevos de los medicamentos pediátricos


Evaluar la seguridad de los medicamentos en niños es extremadamente difícil debido a los procesos de crecimiento y maduración que pueden cambiar la forma en que los niños reaccionan al tratamiento.

Un nuevo estudio identifica los efectos secundarios de los medicamentos en las etapas de desarrollo pediátrico.

Los efectos secundarios de los medicamentos pediátricos representan aproximadamente el 10 % de las hospitalizaciones pediátricas, y casi el 50 % de ellas ponen en peligro la vida. Actualmente hay poca evidencia a pesar de la necesidad de aprender más sobre estos medicamentos y los efectos negativos que pueden tener en los niños.

Aunque los ensayos clínicos continúan siendo el estándar de oro para detectar eventos adversos por medicamentos (ADE) en adultos, plantean preocupaciones éticas y metodológicas cuando se usan en poblaciones pediátricas. Comprender los posibles efectos de varios tratamientos farmacológicos en distintos períodos de la infancia presenta problemas que se ven significativamente exacerbados por los rápidos cambios biológicos y fisiológicos.

Investigadores del Centro Médico Irving de la Universidad de Columbia crearon un algoritmo novedoso que identificó casi 20 000 señales de ADE (información sobre un efecto secundario nuevo o conocido que puede provocar un fármaco específico) a lo largo de las siete etapas de desarrollo pediátrico y las hizo de libre acceso. Este proceso está asistido por un enfoque novedoso que permite que las etapas de desarrollo vecinas mejoren la potencia de detección de señales, lo que le permite superar las limitaciones de datos dentro de las etapas individuales.

Este uso de modelos predictivos en datos del mundo real puede ayudar a abordar un gran vacío en la investigación del cuidado de la salud con respecto a la población pediátrica poco estudiada.

El profesor asociado de DBMI Nicholas Tatonetti y Nick Giangreco, un reciente Ph.D. en Biología de Sistemas. graduarse en[{” attribute=””>Columbia University, recently published their findings in a study published in the journal Med.

“For many reasons, children have historically not been included in clinical trials,” Tatonetti said. “There are many ethical issues around including children in trials, and there are several limitations when children are included that make it difficult to assess the effectiveness and safety of drugs.”

Because of these factors, few drugs are specifically approved for use in children, though once drugs are approved for adults, physicians can prescribe them “off-label” to children.

“Since drugs are not studied and approved in children directly, physicians must rely on guidelines for adults,” he added. “Essentially treating children as if they were simply small adults is oftentimes an incorrect assumption. This study is an attempt to elucidate systematically what the potential side effects are when drugs are used off label in children.”

The study goes beyond simply differentiating side effects in children from those in adults. It focuses on ADEs across seven developmental stages, starting at term neonatal and going through late adolescence, and it is powered by sharing information from neighboring developmental stages. For example, the development of infants and toddlers is close enough that there will be more shared characteristics than there would be for infants and those in early or late adolescence.

“Previously, children were essentially grouped together,” Tatonetti said. “There were only a few studies that just focused on children, and they basically focused on people 18 and under or 21 and under in one group. The innovation here is using known developmental stages and our newly introduced DGAMs (disproportionality generalized additive models) to improve power and enable that analysis.”

Tatonetti stressed that these signals are not validated and are primarily meant for researchers. Parents should consult with their pediatricians on specific drug side effects.

Giangreco, currently a Quantitative Translational Scientist at Regeneron, noted one of several side effects that were identified by this model.

“One we corroborated that the FDA had found was that montelukast, an asthma drug, was found to elicit psychiatric side effects,” he said. “We saw that in our database as well, but we were able to pinpoint certain developmental stages where the risk was more significant, especially the second year of life.”

The study also integrates pediatric enzyme expression data and found that pharmacogenes with dynamic childhood expression are associated with pediatric ADEs.

“This was a biologically-inspired modeling strategy,” Giangreco said. “We used what we knew about biological processes occurring during childhood and formed the modeling strategy. These safety signals came from this prior knowledge of the biological processes that are happening. Our data-driven approach really tried to capture what we thought were the important biologically and physiologically dynamic processes that happen during childhood and use that to tease apart observations across the development stages.”

The model was used on a database of 264,453 pediatric reports in the FDA Adverse Event Reporting System (FAERS). The output of the study is available via KidSIDES, a free and publicly available database of pediatric drug safety signals for the research community, as well as the Pediatric Drug Safety portal (PDSportal), which will facilitate the evaluation of drug safety signals across childhood growth and development.

“The primary intention is for other researchers to use it, to follow up on signals they may observe,” Tatonetti said. “If they are experts on a particular drug usage, or particular disease domain and have observed these types of effects, they could follow up on them and be reassured, or could look at what the other evidence is for that effect as we aggregate it together. Clinicians can use it as a gut check. Maybe they saw an effect, or they are wondering if others are seeing this effect, and they can check the PDSPortal to see if others are seeing this effect or to prompt them to write another case report to the FDA.”

Reference: “A database of pediatric drug effects to evaluate ontogenic mechanisms from child growth and development” by Nicholas P. Giangreco and Nicholas P. Tatonetti, 24 June 2022, Med.
DOI: 10.1016/j.medj.2022.06.001

The study was funded by the National Institutes of Health. 

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