Why the Pediatric Population May Be More Vulnerable to Experiencing Adverse Events from Therapies and Why they May go Unrecognized
WHY THE PEDIATRIC POPULATION MAY
BE MORE VULNERABLE TO EXPERIENCING ADVERSE EVENTS FROM THERAPIES AND WHY THEY
MAY GO UNRECOGNIZED
The
areas unique to pediatrics which increase the probability a child may
experience either an adverse event or have the adverse event remain
unrecognized are of four general types:
·
Differences in the disease process and/or physiol-ogy of
drug disposition because of differences in maturational and developmental
stages of the pedi-atric population;
·
Difficulties in determining an exposure in some earlier
stage of childhood which has a delayed effect on later development or
maturation;
·
Formulation issues, which may encompass prepa-rations or
medication errors because of extempora-neous or compounded preparations, and
exposures to excipients not present in adult preparations; and
·
Communication or recognition oversights because infants,
small children and mentally disabled chil-dren may not be able to articulate
what is wrong and/or the caretakers assume it is part of the normal maladies
that beset childhood development.
1. Differences in
disease process and/or drug phar-macokinetics in children: Children, by
definition, are growing, maturing,
developing and acquiring skills and information. In addition, many enzymatic,
endocrine and metabolic systems and processes have yet to be expressed at the
time the child is exposed to an infection or develops a condition and is given
a therapy. A disease may not manifest itself in the same way in children as in
adults. A high fever in children is more frequently associated with benign
processes than a high fever in adults; adults are usually much more symptomatic
when exposed for the first time to viral infections such a Hepatitis B.
Children have high normal levels of hepatic enzymes and lower levels of
creatinine than adults. To recognize the untoward effects of a therapy, one
must know what is normal and not all physicians and caretakers are aware of all
of the differences in pediatric values for various laboratory tests at the
different stages of pediatric development. Numerous studies now demonstrate
that children at various ages are going to handle a prod-uct’s absorption,
distribution, metabolism and elim-ination differently. Trileptal is an example
where children younger than 4 years of age have an apparent increased clearance
(L/HR/KG) such that they may require twice the dose per body weight compared to
adults. There have been a number of products where younger, pre-school children
have not cleared a prod-uct as rapidly as older children and other products
where the younger children have cleared the prod-uct more rapidly. Clearly
these differences can result in overdosing and an increase in adverse events or
underdosing and a failure to resolve the condition or benefit from the product,
respectively.
2. Ascertainment of
delayed effects of drugs on growth and development: Children are
maturing and chang-ing over a time spectrum. It is difficult to know if any
deviation from the normal process was going to occur independently of any
exposure to a ther-apy. Children are ‘unfinished’ by definition. Attribu-tion
of an exposure to a therapy as the cause of a delay/problem in growth,
development or cognitive abilities is often difficult. We know a certain
percent-age of the pediatric population would experience these problems/delays
without any exposure to any therapy. It is difficult to ascertain if the
child’s problem would have occurred without the exposure, when the ‘base-line’
was not yet established for that particular child. Confounding this issue is
the possibility that an expo-sure in infancy or early childhood may not express
the adverse effect until years later when normally some other maturation event,
such as puberty, was to occur. Long-term studies are not usual in pediatrics
and are very difficult to ‘power’ because there are so many unknowns for each
child and there are many expo-sures occurring over a long duration of time.
3. Pediatric
formulation issues: Formulations are always
a difficult pediatric issue. The excipients required to dissolve solids for
liquid preparations or the materials used for sweetening or masking of
unpleasant tastes may in themselves cause problems. Small amounts of alcohol
may be tolerated in older children but not by infants. Attempts to make
pedi-atric formulations are usually expensive and difficult and sponsors are
not usually enthusiastic to develop these or to market them. Liquid
preparations have a shorter shelf life also. Often pharmacists, care-takers and
parents devise their own preparations. These preparations have usually not been
tested for bioavailability or for interactions with the foods or liquids used
to prepare them. Overdosing, underdos-ing and an increase in frequency of
medication errors occur because of the lack of age-appropriate pediatric
therapies.
4. Unique issues
with recognition, communication and reporting of adverse events in children: Reporting of adverse events for pediatrics is
‘indirect’ and gener-ally involves intermediaries such as parents or
care-takers. The younger the child, the fewer ways he/she can visibly react to
an untoward effect of drugs. An infant’s repertoire of reactions are limited to
physi-cal expressions such as crying, somnolence, vomiting and diarrhea, and
cardiac and respiratory abnormal-ities. It is easy to see why only fairly
impressive adverse effects would be identified by parents or care-takers for
this population. The younger verbal child has a limited vocabulary to express
his or her discom-fort or pain. Because behaviour is normally changing, parents
may be confused or think a child’s behaviour change is normal when it really is
a reaction to a therapy. Even teenagers present a challenge as we know
communication with their parents is not always optimal. In addition, they may
self-medicate and not want their parents to know they are taking certain drugs.
All of these ‘normal’ events or processes that occur in the pediatric
population make ascertainment of adverse effects of therapies even more
difficult than for the adult population. This is particularly relevant to being
able to identify events postmarketing. Parents may not be provided information
about what to look for during the usual therapeutic intervention, as they would
be during the conduct of a trial.
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